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Fiore D, Cappelli LV, Zhaoqi L, Kotlov N, Sorokina M, Phillip J, Zumbo P, Yoffe L, Ghione P, Wang A, Han X, Taylor A, Chiu W, Fragliasso V, Tabbo F, Zamponi N, Di Siervi N, Kayembe C, Medico G, Patel RP, Gaudiano M, Machiorlatti R, Astone G, Cacciapuoti MT, Zanetti G, Pignataro C, Eric RA, Patel S, Zammarchi F, Zanettini C, Queiroz L, Nikitina A, Kudryashova O, Karelin A, Nikitin D, Tychinin D, Postovalova E, Bagaev A, Svekolkin V, Belova E, Tikhonova K, Degryse S, Xu C, Novero D, Ponzoni M, Tiacci E, Falini B, Song J, Khodos I, De Stanchina E, Macari G, Cafforio L, Gardini S, Piva R, Medico E, Ng SY, Moskowitz A, Epstein Z, Intlekofer A, Ahmed D, Chan WC, Martin P, Ruan J, Bertoni F, Foà R, Brody JD, Weinstock DM, Osan J, Santambrogio L, Elemento O, Betel D, Tam W, Ruella M, Cerchietti L, Rabadan R, Horwitz S, Inghirami G. A patient-derived T cell lymphoma biorepository uncovers pathogenetic mechanisms and host-related therapeutic vulnerabilities. Cell Rep Med 2025; 6:102029. [PMID: 40147445 PMCID: PMC12047492 DOI: 10.1016/j.xcrm.2025.102029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Revised: 04/24/2024] [Accepted: 02/21/2025] [Indexed: 03/29/2025]
Abstract
Peripheral T cell lymphomas (PTCLs) comprise heterogeneous malignancies with limited therapeutic options. To uncover targetable vulnerabilities, we generate a collection of PTCL patient-derived tumor xenografts (PDXs) retaining histomorphology and molecular donor-tumor features over serial xenografting. PDX demonstrates remarkable heterogeneity, complex intratumor architecture, and stepwise trajectories mimicking primary evolutions. Combining functional transcriptional stratification and multiparametric imaging, we identify four distinct PTCL microenvironment subtypes with prognostic value. Mechanistically, we discover a subset of PTCLs expressing Epstein-Barr virus-specific T cell receptors and uncover the capacity of cancer-associated fibroblasts of counteracting treatments. PDXs' pre-clinical testing captures individual vulnerabilities, mirrors donor patients' clinical responses, and defines effective patient-tailored treatments. Ultimately, we assess the efficacy of CD5KO- and CD30- Chimeric Antigen Receptor T Cells (CD5KO-CART and CD30_CART, respectively), demonstrating their therapeutic potential and the synergistic role of immune checkpoint inhibitors for PTCL treatment. This repository represents a resource for discovering and validating intrinsic and extrinsic factors and improving the selection of drugs/combinations and immune-based therapies.
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Affiliation(s)
- Danilo Fiore
- Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy; Institute for Experimental Endocrinology and Oncology, "G.Salvatore" IEOS, Consiglio Nazionale delle Ricerche (CNR), 80131 Naples, Italy
| | - Luca Vincenzo Cappelli
- Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA; Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Liu Zhaoqi
- Program for Mathematical Genomics, Department of Systems Biology, Department of Biomedical Informatics, Columbia University, New York, NY 10027 USA; China National Center for Bioinformation, Beijing, China; Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
| | | | | | - Jude Phillip
- Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY 10065 US; Chemical and Biomolecular Engineering, Oncology, Sidney Kimmel Comprehensive Cancer Center, Core Member, Institute for Nanobiotechnology (INBT), Whiting School of Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Paul Zumbo
- Applied Bioinformatics Core, Weill Cornell Medicine, New York, NY 10065, USA; Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10065, US
| | - Liron Yoffe
- Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA; Englander Institute for Precision Medicine, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Paola Ghione
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Anqi Wang
- Program for Mathematical Genomics, Department of Systems Biology, Department of Biomedical Informatics, Columbia University, New York, NY 10027 USA
| | - Xueshuai Han
- Program for Mathematical Genomics, Department of Systems Biology, Department of Biomedical Informatics, Columbia University, New York, NY 10027 USA; China National Center for Bioinformation, Beijing, China; Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
| | - Abigail Taylor
- Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA
| | - William Chiu
- Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA
| | - Valentina Fragliasso
- Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA; Laboratory of translational research, Azienda USL - IRCCS di Reggio Emilia, 42122 Reggio Emila, Italy
| | - Fabrizio Tabbo
- Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA; SC Oncologia ASL CN2 Alba Bra Ospedale Michele e Pietro Ferrero, 12060 Verduno, (CN), Italy
| | - Nahuel Zamponi
- Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY 10065 US
| | - Nicolás Di Siervi
- Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY 10065 US
| | - Clarisse Kayembe
- Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA
| | - Giovanni Medico
- Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA
| | - Ruchi P Patel
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Perelman Center for Advanced Medicine, SPE 8-112, Philadelphia, PA 19104, USA; Division of Hematology-Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Marcello Gaudiano
- Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA
| | - Rodolfo Machiorlatti
- Department of Pathology, Center for Experimental Research and Medical Studies, University of Torino, 10126 Torino, Italy
| | - Giuseppina Astone
- Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA
| | - Maria Teresa Cacciapuoti
- Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA
| | - Giorgia Zanetti
- Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA
| | - Claudia Pignataro
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy
| | - Ruiz Arvin Eric
- Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA
| | - Sanjay Patel
- Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA
| | | | - Claudio Zanettini
- Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA
| | - Lucio Queiroz
- Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA
| | | | | | | | | | | | | | | | | | | | | | | | - Chengqi Xu
- Englander Institute for Precision Medicine, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Domenico Novero
- Division of Pathological Anatomy, Quality and Safety of Diagnosis and Treatment, Città della Salute e della Scienza, 10126 Turin, Italy
| | - Maurilio Ponzoni
- Pathology Unit, San Raffaele Scientific Institute, Milan, Italy; Unit of Lymphoid Malignancies, San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Enrico Tiacci
- Institute of Hematology, University of Perugia, Ospedale S. Maria della Misericordia, S. Andrea delle Fratte, 06156 Perugia Italy
| | - Brunangelo Falini
- Institute of Hematology, University of Perugia, Ospedale S. Maria della Misericordia, S. Andrea delle Fratte, 06156 Perugia Italy
| | - Joo Song
- Department of Pathology, City of Hope Medical Center, Duarte, CA 91010, US
| | - Inna Khodos
- Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, US
| | - Elisa De Stanchina
- Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, US
| | | | | | | | - Roberto Piva
- Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy; Medical Genetics Unit, Città della Salute e della Scienza University Hospital, 10126 Turin, Italy
| | - Enzo Medico
- Department of Oncology, University of Torino, Candiolo, TO, Italy; Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, TO, Italy
| | - Samuel Y Ng
- Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; National Cancer Institute, Bethesda, MD 20892, USA
| | - Allison Moskowitz
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Zachary Epstein
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Andrew Intlekofer
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Dogan Ahmed
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
| | - Wing C Chan
- Department of Pathology, City of Hope Medical Center, Duarte, CA 91010, US
| | - Peter Martin
- Lymphoma Service, Weill Cornell Medical Center, New York, NY 10065, USA
| | - Jia Ruan
- Lymphoma Service, Weill Cornell Medical Center, New York, NY 10065, USA
| | - Francesco Bertoni
- Lymphoma Genomics, Institute of Oncology Research, Faculty of Biomedical Sciences, USI, 6500 Bellinzona, Switzerland; Oncology Institute of Southern Switzerland, EOC,6500 Bellinzona, Switzerland
| | - Robin Foà
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Joshua D Brody
- Department of Medicine, Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, US; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | | | - Jaspreet Osan
- Department of Radiation Oncology, Weill Cornell Medicine, New York, NY 10065, USA
| | - Laura Santambrogio
- Department of Radiation Oncology, Weill Cornell Medicine, New York, NY 10065, USA
| | - Oliver Elemento
- Englander Institute for Precision Medicine, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Doron Betel
- Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY 10065 US; Applied Bioinformatics Core, Weill Cornell Medicine, New York, NY 10065, USA; Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10065, US
| | - Wayne Tam
- Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA; Division of Hematopathology, Northwell Health, New York, NY 11740, USA
| | - Marco Ruella
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Perelman Center for Advanced Medicine, SPE 8-112, Philadelphia, PA 19104, USA; Division of Hematology-Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA; Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Leandro Cerchietti
- Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY 10065 US
| | - Raul Rabadan
- Program for Mathematical Genomics, Department of Systems Biology, Department of Biomedical Informatics, Columbia University, New York, NY 10027 USA
| | - Steven Horwitz
- Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Giorgio Inghirami
- Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA.
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Zhao X, McCall CM, Block JG, Ondrejka SL, Thakral B, Wang SA, Al-Ghamdi Y, Tam W, Coffman B, Foucar K, Daneshpajouhnejad P, Bagg A, Lin F, Hsi ED. Expression of CD6 in Aggressive NK/T-cell Neoplasms and Assessment as a Potential Therapeutic Target: A Bone Marrow Pathology Group Study. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2024; 24:e808-e818. [PMID: 39089930 DOI: 10.1016/j.clml.2024.06.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 06/25/2024] [Accepted: 06/30/2024] [Indexed: 08/04/2024]
Abstract
BACKGROUND Aggressive NK/T-Cell neoplasms are rare hematological malignancies characterized by the abnormal proliferation of NK or NK-like T (NK/T) cells. CD6 is a transmembrane signal transducing receptor involved in lymphocyte activation and differentiation. This study aimed to investigate the CD6 expression in these malignancies and explore the potential of targeting CD6 in these diseases. MATERIALS AND METHODS We conducted a retrospective study with totally 41 cases to investigate the expression of CD6 by immunohistochemistry, including aggressive NK-cell leukemia/lymphoma (ANKLL: N = 10) and extranodal NK/T-cell lymphoma (ENKTL: N = 31). A novel ANKLL model was applied for proof-of-concept functional studies of a CD6 antibody-drug-conjugate (CD6-ADC) both in vitro and in animal trial. RESULTS CD6 was expressed in 68.3% (28/41) of cases (70% (7/10) of ANKLL and 67.7% (21/31) of ENKTL). The median overall survival (OS) for ANKLL and ENTKL cases was 1 and 12 months, respectively, with no significant difference in OS based on CD6 expression (p > 0.05, Kaplan-Meier with log-rank test). In vitro exposure of the CCANKL cell line, derived from an ANKL patient, to an anti-CD6ADC resulted in dose dependent induction of apoptosis. Furthermore, CCANKL engraftment in NSG mice could be blocked by treatment with the anti-CD6 ADC. CONCLUSION To date, this is the first report to explore the expression of CD6 in ANKLL and ENKTL and confirms its expression in the majority of cases. The in vitro and in vivo data support further investigation of CD6 as a potential therapeutic target in these aggressive NK/T-cell malignancies.
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Affiliation(s)
- Xiaoxian Zhao
- Department of Pathology, Wake Forest University School of Medicine, Winston Salem, NC; Department of Laboratory Medicine, Cleveland Clinic, Cleveland OH
| | | | | | - Sarah L Ondrejka
- Department of Laboratory Medicine, Cleveland Clinic, Cleveland OH
| | - Beenu Thakral
- Department of Hematopathology, MD Anderson Cancer Center, Houston, TX
| | - Sa A Wang
- Department of Hematopathology, MD Anderson Cancer Center, Houston, TX
| | - Yahya Al-Ghamdi
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York City, NY
| | - Wayne Tam
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York City, NY
| | - Brittany Coffman
- Department of Pathology, University of New Mexico, Albuquerque, NM
| | - Kathryn Foucar
- Department of Pathology, University of New Mexico, Albuquerque, NM
| | | | - Adam Bagg
- Department of Pathology, University of Pennsylvania, Philadelphia, PA
| | - Feng Lin
- Department of Inflammation & Immunity, Cleveland Clinic, Cleveland OH
| | - Eric D Hsi
- Department of Pathology, Wake Forest University School of Medicine, Winston Salem, NC; Department of Laboratory Medicine, Cleveland Clinic, Cleveland OH; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.
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3
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Shi D, Yang Z, Cai Y, Li H, Lin L, Wu D, Zhang S, Guo Q. Research advances in the molecular classification of gastric cancer. Cell Oncol (Dordr) 2024; 47:1523-1536. [PMID: 38717722 PMCID: PMC11466988 DOI: 10.1007/s13402-024-00951-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/13/2024] [Indexed: 06/27/2024] Open
Abstract
Gastric cancer (GC) is a malignant tumor with one of the lowest five-year survival rates. Traditional first-line treatment regimens, such as platinum drugs, have limited therapeutic efficacy in treating advanced GC and significant side effects, greatly reducing patient quality of life. In contrast, trastuzumab and other immune checkpoint inhibitors, such as nivolumab and pembrolizumab, have demonstrated consistent and reliable efficacy in treating GC. Here, we discuss the intrinsic characteristics of GC from a molecular perspective and provide a comprehensive review of classification and treatment advances in the disease. Finally, we suggest several strategies based on the intrinsic molecular characteristics of GC to aid in overcoming clinical challenges in the development of precision medicine and improve patient prognosis.
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Affiliation(s)
- Dike Shi
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Jiefang Road, Hangzhou, 310009, China
| | - Zihan Yang
- Department of Gastroenterology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Yanna Cai
- Department of Gastroenterology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Hongbo Li
- Department of Gastroenterology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Lele Lin
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Jiefang Road, Hangzhou, 310009, China
| | - Dan Wu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Jiefang Road, Hangzhou, 310009, China
| | - Shengyu Zhang
- Department of Gastroenterology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Qingqu Guo
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Jiefang Road, Hangzhou, 310009, China.
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Chang YC, Tsai HJ, Huang TY, Su NW, Su YW, Chang YF, Chen CGS, Lin J, Chang MC, Chen SJ, Chen HC, Lim KH, Chang KC, Kuo SH. Analysis of mutation profiles in extranodal NK/T-cell lymphoma: clinical and prognostic correlations. Ann Hematol 2024; 103:2917-2930. [PMID: 38671297 DOI: 10.1007/s00277-024-05698-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 03/03/2024] [Indexed: 04/28/2024]
Abstract
The molecular pathogenesis of extranodal NK/T-cell lymphoma (NKTCL) remains obscured despite the next-generation sequencing (NGS) studies explored on ever larger cohorts in the last decade. We addressed the highly variable mutation frequencies reported among previous studies with comprehensive amplicon coverage and enhanced sequencing depth to achieve higher genomic resolution for novel genetic discovery and comparative mutational profiling of the oncogenesis of NKTCL. Targeted exome sequencing was conducted to interrogate 415 cancer-related genes in a cohort of 36 patients with NKTCL, and a total of 548 single nucleotide variants (SNVs) and 600 Copy number variances (CNVs) were identified. Recurrent amplification of the MCL1 (67%) and PIM1 (56%) genes was detected in a dominant majority of patients in our cohort. Functional mapping of genetic aberrations revealed that an enrichment of mutations in the JAK-STAT signaling pathway, including the cytokine receptor LIFR (copy number loss) upstream of JAK3, STAT3 (activating SNVs), and downstream effectors of MYC, PIM1 and MCL1 (copy number gains). RNA in situ hybridization showed the significant consistence of MCL1 RNA level and copy number of MCL1 gene. We further correlated molecular and clinical parameters with overall survival (OS) of these patients. When correlations were analyzed by univariate followed by multivariate modelling, only copy number loss of LIFR gene and stage (III-IV) were independent prognostic factors of reduced OS. Our findings identified that novel loss of LIFR gene significantly correlated with the adverse clinical outcome of NKTCL patients and provided therapeutic opportunities for this disease through manipulating LIFR.
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Affiliation(s)
- Yu-Cheng Chang
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan
- Division of Hematology and Oncology, Department of Internal Medicine, MacKay Memorial Hospital, No. 92, Section 2, Zhongshan North Road, New Taipei City, 10449, Taiwan
- Department of Medicine, MacKay Medical College, New Taipei City, Taiwan
- Laboratory of Good Clinical Research Center, Department of Medical Research, MacKay Memorial Hospital, Tamsui District, New Taipei City, Taiwan
| | - Hui-Jen Tsai
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
- Department of Oncology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - To-Yu Huang
- Laboratory of Good Clinical Research Center, Department of Medical Research, MacKay Memorial Hospital, Tamsui District, New Taipei City, Taiwan
| | - Nai-Wen Su
- Division of Hematology and Oncology, Department of Internal Medicine, MacKay Memorial Hospital, No. 92, Section 2, Zhongshan North Road, New Taipei City, 10449, Taiwan
- Department of Medicine, MacKay Medical College, New Taipei City, Taiwan
- Laboratory of Good Clinical Research Center, Department of Medical Research, MacKay Memorial Hospital, Tamsui District, New Taipei City, Taiwan
| | - Ying-Wen Su
- Division of Hematology and Oncology, Department of Internal Medicine, MacKay Memorial Hospital, No. 92, Section 2, Zhongshan North Road, New Taipei City, 10449, Taiwan
- Department of Medicine, MacKay Medical College, New Taipei City, Taiwan
- Laboratory of Good Clinical Research Center, Department of Medical Research, MacKay Memorial Hospital, Tamsui District, New Taipei City, Taiwan
- Department of Nursing, Nursing, and Management, MacKay Junior College of Medicine, New Taipei City, Taiwan
| | - Yi-Fang Chang
- Division of Hematology and Oncology, Department of Internal Medicine, MacKay Memorial Hospital, No. 92, Section 2, Zhongshan North Road, New Taipei City, 10449, Taiwan
- Department of Medicine, MacKay Medical College, New Taipei City, Taiwan
- Laboratory of Good Clinical Research Center, Department of Medical Research, MacKay Memorial Hospital, Tamsui District, New Taipei City, Taiwan
| | - Caleb Gon-Shen Chen
- Division of Hematology and Oncology, Department of Internal Medicine, MacKay Memorial Hospital, No. 92, Section 2, Zhongshan North Road, New Taipei City, 10449, Taiwan
- Department of Medicine, MacKay Medical College, New Taipei City, Taiwan
- Laboratory of Good Clinical Research Center, Department of Medical Research, MacKay Memorial Hospital, Tamsui District, New Taipei City, Taiwan
- Department of Nursing, Nursing, and Management, MacKay Junior College of Medicine, New Taipei City, Taiwan
- Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan
| | - Johnson Lin
- Division of Hematology and Oncology, Department of Internal Medicine, MacKay Memorial Hospital, No. 92, Section 2, Zhongshan North Road, New Taipei City, 10449, Taiwan
| | - Ming-Chih Chang
- Division of Hematology and Oncology, Department of Internal Medicine, MacKay Memorial Hospital, No. 92, Section 2, Zhongshan North Road, New Taipei City, 10449, Taiwan
- Department of Medicine, MacKay Medical College, New Taipei City, Taiwan
| | | | | | - Ken-Hong Lim
- Division of Hematology and Oncology, Department of Internal Medicine, MacKay Memorial Hospital, No. 92, Section 2, Zhongshan North Road, New Taipei City, 10449, Taiwan.
- Department of Medicine, MacKay Medical College, New Taipei City, Taiwan.
- Laboratory of Good Clinical Research Center, Department of Medical Research, MacKay Memorial Hospital, Tamsui District, New Taipei City, Taiwan.
| | - Kung-Chao Chang
- Department of Pathology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan.
| | - Sung-Hsin Kuo
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan.
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
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Wang W, Zhang A, Li Y, Wang D, Chen L, Li Q, Chen J, Li H, Sun S, Pan M, Zhou W, Wu H. Clinical, pathological, and molecular features of central nervous system tumors with BCOR internal tandem duplication. Pathol Res Pract 2024; 259:155367. [PMID: 38797130 DOI: 10.1016/j.prp.2024.155367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 04/09/2024] [Accepted: 05/23/2024] [Indexed: 05/29/2024]
Abstract
Central nervous system tumor with BCOR internal tandem duplication (CNS tumor with BCOR-ITD) constitutes a molecularly distinct entity, characterized by internal tandem duplication within exon 15 of the BCOR transcriptional co-repressor gene (BCOR-ITD). The current study aimed to elucidate the clinical, pathological, and molecular attributes of CNS tumors with BCOR-ITD and explore their putative cellular origin. This study cohort comprised four pediatric cases, aged 23 months to 13 years at initial presentation. Magnetic resonance imaging revealed large, well-circumscribed intra-CNS masses localized heterogeneously throughout the CNS. Microscopically, tumors were composed of spindle to ovoid cells, exhibiting perivascular pseudorosettes and palisading necrosis, but lacking microvascular proliferation. Immunohistochemical staining showed diffuse tumor cell expression of BCOR, CD56, CD99, vimentin, and the stem cell markers PAX6, SOX2, CD133 and Nestin, alongside focal positivity for Olig-2, S100, SOX10, Syn and NeuN. Molecularly, all cases harbored BCOR-ITDs ranging from 87 to 119 base pairs in length, including one case with two distinct ITDs. Notably, the ITDs were interrupted by unique 1-3 bp insertions in all cases. In summary, CNS tumors with BCOR-ITD exhibit characteristic clinical, pathological, and molecular features detectable through BCOR immunohistochemistry and confirmatory molecular analyses. Their expression of stem cell markers raises the possibility of an origin from neuroepithelial stem cells rather than representing true embryonal neoplasms.
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Affiliation(s)
- Wei Wang
- Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Intelligent Pathology Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Anli Zhang
- Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Intelligent Pathology Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Yujie Li
- Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Intelligent Pathology Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Daizhong Wang
- Department of Pathology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Lian Chen
- Department of Pathology, Children's Hospital of Fudan University, Shanghai, China
| | - Qianqian Li
- Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Intelligent Pathology Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Jingjing Chen
- Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Intelligent Pathology Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Heng Li
- Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Intelligent Pathology Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Sibai Sun
- Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Intelligent Pathology Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Minhong Pan
- Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
| | - Wenchao Zhou
- Intelligent Pathology Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
| | - Haibo Wu
- Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Intelligent Pathology Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
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6
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Le MK, Oishi N, Satou A, Miyaoka M, Kawashima I, Mochizuki K, Kirito K, Feldman AL, Nakamura N, Kondo T. Molecular and clinicopathological features of granzyme B-negative extranodal NK/T-cell lymphoma. Hum Pathol 2024; 143:10-16. [PMID: 38000677 DOI: 10.1016/j.humpath.2023.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 11/13/2023] [Accepted: 11/17/2023] [Indexed: 11/26/2023]
Abstract
Extranodal NK/T-cell lymphoma (ENKTL) generally expresses cytotoxic molecules, including granzyme B (GZMB), T-cell-restricted intracellular antigen-1 (TIA-1), and perforin; however, the expression of these molecules varies across cases. We performed gene expression profiling and identified unique biological and clinicopathological features of GZMB-negative ENKTL. We reviewed the clinicopathological characteristics of 71 ENKTL samples. Gene expression profiling on nine ENKTLs using multiplexed, direct, and digital mRNA quantification divided ENKTLs into Groups A (n = 7) and B (n = 2) through hierarchical clustering and t-distributed stochastic neighbor embedding. Group B was characterized by downregulation of genes associated with IL6-JAK-STAT3 signaling and inflammatory responses. GZMB mRNA expression was significantly downregulated in Group B. GZMB protein expression was evaluated with immunohistochemistry in all 71 ENKTLs, and expression data of Tyr705-phosphorylated STAT3 (pSTAT3) and MYC from our previous study was utilized. T-cell receptor gamma (TRG) gene rearrangement in the selected samples was also assessed using PCR. GZMB expression was higher in pSTAT3-positive (p = 0.028) and MYC-positive (p = 0.014) ENKTLs. Eighteen percent (13/71) of all ENKTLs were negative for GZMB (defined by positivity <10 %); patients with GZMB-negative ENKTLs were often in a higher clinical stage (p = 0.016). We observed no other correlations with clinical parameters or TRG rearrangement and no significant association between GZMB expression and survival. In conclusion, GZMB expression is highly heterogeneous in ENKTLs and is associated with the activation of the JAK-STAT3 pathway and higher MYC expression. GZMB-negative ENKTLs correlate with an advanced clinical stage, suggesting the potential utility of GZMB immunohistochemistry as a biomarker of ENKTL.
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Affiliation(s)
- Minh-Khang Le
- Department of Pathology, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan
| | - Naoki Oishi
- Department of Pathology, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan.
| | - Akira Satou
- Department of Surgical Pathology, Aichi Medical University Hospital, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Masashi Miyaoka
- Department of Pathology, Tokai University, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan
| | - Ichiro Kawashima
- Department of Hematology and Oncology, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan
| | - Kunio Mochizuki
- Department of Pathology, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan
| | - Keita Kirito
- Department of Hematology and Oncology, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan
| | - Andrew L Feldman
- Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA
| | - Naoya Nakamura
- Department of Pathology, Tokai University, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan
| | - Tetsuo Kondo
- Department of Pathology, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan
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7
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Shareena G, Kumar D. Epigenetics of Epstein Barr virus - A review. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166838. [PMID: 37544529 DOI: 10.1016/j.bbadis.2023.166838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 07/14/2023] [Accepted: 07/31/2023] [Indexed: 08/08/2023]
Abstract
Epstein Barr is the first-in-human oncogenic virus, closely related to numerous lymphoproliferative and malignant diseases, including HL, BL, NPC, and GC. EBV establishes life-long persistence infection portraying a biphasic viral life cycle: latent period and lytic replication. B-cells serve as critical regions for EBV latent genes, wherein viral gene expression is suppressed, promoting viral genome maintenance and immune recognition evasion. Upon its lytic reactivation, viral gene expression induces its replication, progeny production, and transmission. Dysregulations of epigenetic regulation in expressions of TSGs lead to carcinogenesis. Several studies reveal that EBV is associated with aberrant viral DNA and host genome methylation patterns, promoting immune monitoring, recognition evasiveness and host cell persistence. Among other epigenetic modifications, DNA methylation suppresses the majority of viral latent gene promoters, sparing a few, and acts as a prerequisite for activating EBV's lytic cycle, giving rise to viral progeny. It affects the host's epigenome via reprogramming cells to oncogenic, long-lasting phenotypes, as evident in several malignancies. At each phase of its life cycle, EBV exploits cellular mechanisms of epigenetic regulation, implying its unique host-pathogen relationship. This review summarized the DNA methylation's regulatory roles on several EBV-related promoter regions, along with the host genome in pathological conditions, highlights viral genes involved in a latent, lytic and latent-lytic phase of EBV infection. Moreover, it provides diagrammatic insights into methylation-based pathways in EBV.
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Affiliation(s)
- Gadde Shareena
- Poona College of Pharmacy, Department of Pharmaceutical Chemistry, Bharati Vidyapeeth (Deemed to be University), Erandwane, Pune 411038, Maharashtra, India
| | - Dileep Kumar
- Poona College of Pharmacy, Department of Pharmaceutical Chemistry, Bharati Vidyapeeth (Deemed to be University), Erandwane, Pune 411038, Maharashtra, India; UC Davis Comprehensive Cancer Center, Department of Entomology and Nematology, University of California Davis, One Shields Avenue, Davis, CA 95616, USA.
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8
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Hiratsuka T, Ito S, Sakai R, Yokose T, Endo T, Daigo Y, Miyagi Y, Tsuruyama T. Proteome analysis of CD5-positive diffuse large B cell lymphoma FFPE tissue reveals downregulation of DDX3X, DNAJB1, and B cell receptor signaling pathway proteins including BTK and Immunoglobulins. Clin Proteomics 2023; 20:36. [PMID: 37705009 PMCID: PMC10498596 DOI: 10.1186/s12014-023-09422-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 07/25/2023] [Indexed: 09/15/2023] Open
Abstract
BACKGROUND The molecular pathology of diffuse large B cell lymphoma (DLBCL) has been extensively studied. Among DLBCL subtypes, the prognosis of CD5-positive DLBCL is worse than that of CD5-negative DLBCL, considering the central nervous system relapse and poor response to R-CHOP therapy. However, the molecular mechanisms underlying the tumorigenesis and progression of CD5-positive DLBCL remain unknown. METHODS To identify molecular markers that can be targeted for treating DLBCL, a proteomic study was performed using liquid chromatography-mass spectrometry with chemically pretreated formalin-fixed paraffin-embedded specimens from CD5-positive (n = 5) and CD5-negative DLBCL patients (n = 6). RESULTS Twenty-one proteins showed significant downregulation in CD5-positive DLBCL compared to CD5-negative DLBCL. Principal component analysis of protein expression profiling in CD5-positive and CD5-negative DLBCL revealed that DNAJB1, DDX3X, and BTK, which is one of the B cell phenotypic proteins, were the most significantly downregulated proteins and served as biomarkers that distinguished both groups. Additionally, a set of immunoglobulins, including IgG4, exhibited significant downregulation. Immunohistochemistry analysis for BTK demonstrated reduced staining in CD5-positive DLBCL compared to CD5-negative DLBCL. CONCLUSIONS In conclusion, DNAJB1 and DDX3X, BTK, and a set of immunoglobulins are promising biomarkers. Probably, the suppression of BCR signaling is the unique phenotype of CD5-positive DLBCL. This formalin-fixed paraffin-embedded (FFPE)-based profiling may help to develop novel therapeutic molecularly targeted drugs for treating DLBCL.
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Affiliation(s)
- Takuya Hiratsuka
- Department of Drug Discovery Medicine, Pathology Division, Kyoto University Graduate School of Medicine, Kyoto, Japan.
| | - Shinji Ito
- Medical Research Support Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Rika Sakai
- Department of Oncology, Kanagawa Cancer Center Research Institute, Yokohama, Japan
| | - Tomoyuki Yokose
- Department of Pathology, Kanagawa Cancer Center Research Institute, Yokohama, Japan
| | - Tatsuya Endo
- Department of Physics, Graduate School of Science, Tohoku University, Sendai, Japan
| | - Yataro Daigo
- Department of Medical Oncology, Cancer Center, and Center for Advanced Medicine Against Cancer, Shiga University of Medical Science, Otsu, Japan
- Center for Antibody and Vaccine Therapy, Research Hospital, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Yohei Miyagi
- Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan
| | - Tatsuaki Tsuruyama
- Department of Drug Discovery Medicine, Pathology Division, Kyoto University Graduate School of Medicine, Kyoto, Japan.
- Department of Physics, Graduate School of Science, Tohoku University, Sendai, Japan.
- Tazuke-Kofukai Medical Institute Kitano Hospital, Ogimachi, Osaka, Japan.
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9
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Gadek M, Sherr EH, Floor SN. The variant landscape and function of DDX3X in cancer and neurodevelopmental disorders. Trends Mol Med 2023; 29:726-739. [PMID: 37422363 DOI: 10.1016/j.molmed.2023.06.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 06/12/2023] [Accepted: 06/14/2023] [Indexed: 07/10/2023]
Abstract
RNA molecules rely on proteins across their life cycle. DDX3X encodes an X-linked DEAD-box RNA helicase with a Y-linked paralog, DDX3Y. DDX3X is central to the RNA life cycle and is implicated in many conditions, including cancer and the neurodevelopmental disorder DDX3X syndrome. DDX3X-linked conditions often exhibit sex differences, possibly due to differences between expression or function of the X- and Y-linked paralogs DDX3X and DDX3Y. DDX3X-related diseases have different mutational landscapes, indicating different roles of DDX3X. Understanding the role of DDX3X in normal and disease states will inform the understanding of DDX3X in disease. We review the function of DDX3X and DDX3Y, discuss how mutation type and sex bias contribute to human diseases involving DDX3X, and review possible DDX3X-targeting treatments.
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Affiliation(s)
- Margaret Gadek
- Department of Cell and Tissue Biology, University of California, San Francisco, CA 94143, USA
| | - Elliott H Sherr
- Department of Neurology, University of California, San Francisco, CA 94143, USA
| | - Stephen N Floor
- Department of Cell and Tissue Biology, University of California, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA.
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10
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Costa RDO, Pereira J, Lage LADPC, Baiocchi OCG. Extranodal NK-/T-cell lymphoma, nasal type: what advances have been made in the last decade? Front Oncol 2023; 13:1175545. [PMID: 37529691 PMCID: PMC10388588 DOI: 10.3389/fonc.2023.1175545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 06/26/2023] [Indexed: 08/03/2023] Open
Abstract
Extranodal NK-/T-cell lymphoma (ENKTCL) is a rare and highly aggressive malignancy with significant racial and geographic variations worldwide. In addition to the formerly "nasal-type" initial description, these lymphomas are predominantly extranodal in origin and typically cause vascular damage and tissue destruction, and although not fully understood, Epstein-Barr virus (EBV) has an important role in its pathogenesis. Initial assessment must include a hematopathology review of representative and viable tumor areas without necrosis for adequate immunohistochemistry studies, including EBV-encoded small RNA (EBER) in situ hybridization (ISH). Positron emission tomography with 18-fluorodeoxyglucose (18F-FDG-PET/CT) for accurate staging is essential, and most patients will have localized disease (IE/IIE) at diagnosis. Apart from other T-cell malignancies, the best treatment even for localized cases is combined modality therapy (chemotherapy plus radiotherapy) with non-anthracycline-based regimens. For advanced-stage disease, l-asparaginase-containing regimens have shown improved survival, but relapsed and refractory cases have very poor outcomes. Nowadays, even with a better understanding of pathogenic pathways, up-front therapy is completely based on chemotherapy and radiotherapy, and treatment-related mortality is not low. Future strategies targeting signaling pathways and immunotherapy are evolving, but we need to better identify those patients with dismal outcomes in a pre-emptive way. Given the rarity of the disease, international collaborations are urgently needed, and clinical trials are the way to change the future.
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Affiliation(s)
- Renata de Oliveira Costa
- Department of Hematology, Faculdade de Ciências Médicas de Santos (FCMS), Centro Universitário Lusíadas (Unilus), Santos, São Paulo, Brazil
- Hospital Alemao Osvaldo Cruz (HAOC), São Paulo, Brazil
| | - Juliana Pereira
- Hospital Alemao Osvaldo Cruz (HAOC), São Paulo, Brazil
- Department of Hematology, Hemotherapy and Cell Therapy, Faculdade de Medicina da Universidade de Sao Paulo (FM-USP), São Paulo, Brazil
- Laboratory of Medical Investigation in Pathogenesis and Directed Therapy in Onco-Immuno-Hematology (LIM-31), University of Sao Paulo (USP), São Paulo, Brazil
| | - Luís Alberto de Pádua Covas Lage
- Department of Hematology, Hemotherapy and Cell Therapy, Faculdade de Medicina da Universidade de Sao Paulo (FM-USP), São Paulo, Brazil
- Laboratory of Medical Investigation in Pathogenesis and Directed Therapy in Onco-Immuno-Hematology (LIM-31), University of Sao Paulo (USP), São Paulo, Brazil
| | - Otávio César Guimarães Baiocchi
- Hospital Alemao Osvaldo Cruz (HAOC), São Paulo, Brazil
- Department of Hematology, Universidade Federal de Sao Paulo (Unifesp), São Paulo, Brazil
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11
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Yamashita T, Hotta J, Jogu Y, Sakai E, Ono C, Bamba H, Suzuki H, Yamada M, Takenouchi T, Kosaki K, Yorifuji T, Hamazaki T, Seto T. Oculofaciocardiodental syndrome caused by a novel BCOR variant. Hum Genome Var 2023; 10:18. [PMID: 37308473 PMCID: PMC10261115 DOI: 10.1038/s41439-023-00244-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 04/14/2023] [Accepted: 04/20/2023] [Indexed: 06/14/2023] Open
Abstract
Oculofaciocardiodental syndrome is caused by variants in the BCL6 corepressor (BCOR) gene. We identified a novel heterozygous frameshift variant, NM_001123385.2(BCOR):c.2326del, that arose de novo in a Japanese girl with characteristic facial features, congenital heart disease, bilateral syndactyly of toes 2 and 3, congenital cataracts, dental abnormalities, and mild intellectual disability. Reports of BCOR variants are rare, and further case accumulation is warranted.
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Affiliation(s)
- Tomoyo Yamashita
- Department of Medical Genetics, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
- Department of Pediatrics, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Junko Hotta
- Department of Medical Genetics, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
- Department of Pediatrics, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Yukiko Jogu
- Department of Medical Genetics, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Eri Sakai
- Department of Medical Genetics, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Chie Ono
- Department of Medical Genetics, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Haruka Bamba
- Department of Medical Genetics, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Hisato Suzuki
- Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan
| | - Mamiko Yamada
- Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan
| | - Toshiki Takenouchi
- Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan
| | - Kenjiro Kosaki
- Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan
| | - Tohru Yorifuji
- Division of Pediatric Endocrinology and Metabolism, Children's Medical Center, Osaka City General Hospital, Osaka, Japan
| | - Takashi Hamazaki
- Department of Pediatrics, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Toshiyuki Seto
- Department of Medical Genetics, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan.
- Department of Pediatrics, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan.
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12
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Major A, Porcu P, Haverkos BM. Rational Targets of Therapy in Extranodal NK/T-Cell Lymphoma. Cancers (Basel) 2023; 15:cancers15051366. [PMID: 36900160 PMCID: PMC10000128 DOI: 10.3390/cancers15051366] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 02/09/2023] [Accepted: 02/14/2023] [Indexed: 02/24/2023] Open
Abstract
Extranodal NK/T-cell lymphoma (ENKTL) is an aggressive extranodal non-Hodgkin lymphoma (NHL) with poor outcomes, particularly in advanced-stage and relapsed/refractory disease. Emerging research on molecular drivers of ENKTL lymphomagenesis by next-generation and whole genome sequencing has revealed diverse genomic mutations in multiple signaling pathways, with the identification of multiple putative targets for novel therapeutic agents. In this review, we summarize the biological underpinnings of newly-understood therapeutic targets in ENKTL with a focus on translational implications, including epigenetic and histone regulatory aberrations, activation of cell proliferation signaling pathways, suppression of apoptosis and tumor suppressor genes, changes in the tumor microenvironment, and EBV-mediated oncogenesis. In addition, we highlight prognostic and predictive biomarkers which may enable a personalized medicine approach toward ENKTL therapy.
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Affiliation(s)
- Ajay Major
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Pierluigi Porcu
- Division of Medical Oncology and Hematopoietic Stem Cell Transplantation, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Bradley M. Haverkos
- Division of Hematology, University of Colorado School of Medicine, Aurora, CO 80045, USA
- Correspondence: ; Tel.: +1-720-848-0414
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13
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Andrades A, Peinado P, Alvarez-Perez JC, Sanjuan-Hidalgo J, García DJ, Arenas AM, Matia-González AM, Medina PP. SWI/SNF complexes in hematological malignancies: biological implications and therapeutic opportunities. Mol Cancer 2023; 22:39. [PMID: 36810086 PMCID: PMC9942420 DOI: 10.1186/s12943-023-01736-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 01/30/2023] [Indexed: 02/23/2023] Open
Abstract
Hematological malignancies are a highly heterogeneous group of diseases with varied molecular and phenotypical characteristics. SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling complexes play significant roles in the regulation of gene expression, being essential for processes such as cell maintenance and differentiation in hematopoietic stem cells. Furthermore, alterations in SWI/SNF complex subunits, especially in ARID1A/1B/2, SMARCA2/4, and BCL7A, are highly recurrent across a wide variety of lymphoid and myeloid malignancies. Most genetic alterations cause a loss of function of the subunit, suggesting a tumor suppressor role. However, SWI/SNF subunits can also be required for tumor maintenance or even play an oncogenic role in certain disease contexts. The recurrent alterations of SWI/SNF subunits highlight not only the biological relevance of SWI/SNF complexes in hematological malignancies but also their clinical potential. In particular, increasing evidence has shown that mutations in SWI/SNF complex subunits confer resistance to several antineoplastic agents routinely used for the treatment of hematological malignancies. Furthermore, mutations in SWI/SNF subunits often create synthetic lethality relationships with other SWI/SNF or non-SWI/SNF proteins that could be exploited therapeutically. In conclusion, SWI/SNF complexes are recurrently altered in hematological malignancies and some SWI/SNF subunits may be essential for tumor maintenance. These alterations, as well as their synthetic lethal relationships with SWI/SNF and non-SWI/SNF proteins, may be pharmacologically exploited for the treatment of diverse hematological cancers.
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Affiliation(s)
- Alvaro Andrades
- grid.4489.10000000121678994Department of Biochemistry and Molecular Biology I. Faculty of Sciences, University of Granada, Granada, Spain ,grid.470860.d0000 0004 4677 7069GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, Granada, Spain ,grid.507088.2Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain
| | - Paola Peinado
- grid.4489.10000000121678994Department of Biochemistry and Molecular Biology I. Faculty of Sciences, University of Granada, Granada, Spain ,grid.470860.d0000 0004 4677 7069GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, Granada, Spain ,grid.507088.2Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain ,grid.451388.30000 0004 1795 1830Present Address: The Francis Crick Institute, London, UK
| | - Juan Carlos Alvarez-Perez
- grid.4489.10000000121678994Department of Biochemistry and Molecular Biology I. Faculty of Sciences, University of Granada, Granada, Spain ,grid.470860.d0000 0004 4677 7069GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, Granada, Spain ,grid.507088.2Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain
| | - Juan Sanjuan-Hidalgo
- grid.4489.10000000121678994Department of Biochemistry and Molecular Biology I. Faculty of Sciences, University of Granada, Granada, Spain ,grid.470860.d0000 0004 4677 7069GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, Granada, Spain
| | - Daniel J. García
- grid.470860.d0000 0004 4677 7069GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, Granada, Spain ,grid.4489.10000000121678994Department of Biochemistry and Molecular Biology III and Immunology, University of Granada, Granada, Spain
| | - Alberto M. Arenas
- grid.4489.10000000121678994Department of Biochemistry and Molecular Biology I. Faculty of Sciences, University of Granada, Granada, Spain ,grid.470860.d0000 0004 4677 7069GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, Granada, Spain ,grid.507088.2Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain
| | - Ana M. Matia-González
- grid.4489.10000000121678994Department of Biochemistry and Molecular Biology I. Faculty of Sciences, University of Granada, Granada, Spain ,grid.470860.d0000 0004 4677 7069GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, Granada, Spain ,grid.507088.2Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain
| | - Pedro P. Medina
- grid.4489.10000000121678994Department of Biochemistry and Molecular Biology I. Faculty of Sciences, University of Granada, Granada, Spain ,grid.470860.d0000 0004 4677 7069GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, Granada, Spain ,grid.507088.2Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain
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14
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Samad MA, Mahboob E, Shafiq A, Ur Rehman MH, Sheikh A, Tharwani ZH. Types of T-cell lymphoma-a cytogenetic perspective. Ann Med Surg (Lond) 2022; 84:104844. [PMID: 36536747 PMCID: PMC9758356 DOI: 10.1016/j.amsu.2022.104844] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 09/25/2022] [Accepted: 10/30/2022] [Indexed: 11/11/2022] Open
Abstract
T cell lymphoma, a type of non-Hodgkin lymphomas is a rare form of malignancy with poor outcomes. TCLS are a heterogeneous group of lymphoid malignancies that occur in nodal and extranodal sites. There are two main types of TCLs namely T-lymphoblastic lymphoma/leukemia and Peripheral T-cell lymphomas classified based on clinical manifestations and cytogenetic mutations. The use of advance technology like karyotyping, fluorescent in situ hybridization (FISH), comparative genomic hybridization (CGH) has allowed us to study TCLs in detail and to observe a different biochemical change that occurs in different TCLs allowing us to classify and treat them differently. This review focuses on the different mutations occurring in different TCLs and how they help us distinguish one type from another.
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Affiliation(s)
- Muhammad Ammar Samad
- Faculty of Medicine, Dow Medical College, Dow University of Health Sciences, Karachi, Pakistan
| | - Eman Mahboob
- Faculty of Medicine, Dow Medical College, Dow University of Health Sciences, Karachi, Pakistan
| | - Aimen Shafiq
- Faculty of Medicine, Dow Medical College, Dow University of Health Sciences, Karachi, Pakistan
| | | | - Ayesha Sheikh
- Faculty of Medicine, Dow Medical College, Dow University of Health Sciences, Karachi, Pakistan
| | - Zoaib Habib Tharwani
- Faculty of Medicine, Dow Medical College, Dow University of Health Sciences, Karachi, Pakistan
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15
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High-dose extended-field radiotherapy plus chemotherapy improved survival in extranodal NK/T-cell lymphoma in a real-life setting: results from the multicenter T-Cell Brazil Project. Sci Rep 2022; 12:20557. [PMID: 36446856 PMCID: PMC9709053 DOI: 10.1038/s41598-022-25034-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 11/23/2022] [Indexed: 11/30/2022] Open
Abstract
Extranodal natural-killer/T-cell lymphoma (ENKTL) is a rare and aggressive Epstein-Barr virus related mature T-cell and natural-killer malignancy. Although highly prevalent in South America, few studies covering data from this geographic location have been published. Therefore, this study aims to report clinical characteristics, prognostic factors, and outcomes in a multicenter cohort of ENKTL patients from Brazil. This retrospective, observational and multicenter study included 98 ENKTL patients treated during two decades in Brazil. Data were extracted from the T-Cell Brazil Project database. In our cohort, 59/98 patients (60.2%) were male, with a median age of 50 years. Sixty-two patients (63.3%) had B-symptoms, 26/98 (26.5%) had Eastern Cooperative Oncology Group scale ≥ 2; 16/98 (16.3%) presented extranasal disease and 34.7% (34/98) were advanced-stage (Ann Arbor/Cotswolds III/IV). The median follow-up for the whole cohort was 49 months, with an estimated 2-year overall survival (OS) and progression-free survival (PFS) of 51.1% and 17.7%, respectively. In early-stage disease (IE/IIE), the median OS was 21.8 months for patients treated with concurrent radiotherapy plus chemotherapy (CCRT-VIPD [etoposide/vp-16, ifosfamide, cisplatin and dexamethasone), 16.2 months for sequential chemoradiotherapy (SCRT) followed by asparaginase-based regimens, and 56.7 months for SCRT followed by CHOP-like (cyclophosphamide, doxorrubicin, vincristine and prednisone) treatments, p = 0.211. CCRT was associated with higher rates of early-mortality, hematological toxicity, and mucositis. Median OS was 8.2 months for patients with advanced-stage disease receiving regimens containing asparaginase compared to 3.2 months for anthracycline-based therapy, p = 0.851. Chemo-radiotherapy (CRT) regimens demonstrated better OS (p = 0.001) and PFS (p = 0.007) than chemotherapy alone. Multivariate analysis revealed anemia, relapsed/refractory (R/R) disease and radiotherapy omission as poor outcome predictors for OS. Lymphopenia and radiotherapy omission adversely affected PFS. Concerning progression of disease within 24-months (POD-24), clinical stage III/IV was a poor outcome predictor. In this real-life Brazilian cohort, ENKTL presented dismal outcomes. Radiation therapy was an independent factor for increased OS and PFS, but CCRT regimens were associated with higher toxicities. Polychemotherapy based on anti-multi drug resistant agents was not associated with survival benefit in either early or advanced-stage disease in our patient cohort.
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16
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Bakr FS, Whittaker SJ. Advances in the understanding and treatment of Cutaneous T-cell Lymphoma. Front Oncol 2022; 12:1043254. [PMID: 36505788 PMCID: PMC9729763 DOI: 10.3389/fonc.2022.1043254] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 10/19/2022] [Indexed: 11/25/2022] Open
Abstract
Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of non-Hodgkin's lymphomas (NHL) characterised by the clonal proliferation of malignant, skin homing T-cells. Recent advances have been made in understanding the molecular pathogenesis of CTCL. Multiple deep sequencing studies have revealed a complex genomic landscape with large numbers of novel single nucleotide variants (SNVs) and copy number variations (CNVs). Commonly perturbed genes include those involved in T-cell receptor signalling, T-cell proliferation, differentiation and survival, epigenetic regulators as well as genes involved in genome maintenance and DNA repair. In addition, studies in CTCL have identified a dominant UV mutational signature in contrast to systemic T-cell lymphomas and this likely contributes to the high tumour mutational burden. As current treatment options for advanced stages of CTCL are associated with short-lived responses, targeting these deregulated pathways could provide novel therapeutic approaches for patients. In this review article we summarise the key pathways disrupted in CTCL and discuss the potential therapeutic implications of these findings.
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17
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Dong G, Liu X, Wang L, Yin W, Bouska A, Gong Q, Shetty K, Chen L, Sharma S, Zhang J, Lome-Maldonado C, Quintanilla-Martinez L, Li Y, Song JY, Zhang W, Shi Y, Wang J, Kong L, Wu X, Wang J, Liu HG, Kong L, Sun W, Liu W, Wang L, McKeithan TW, Iqbal J, Chan WC. Genomic profiling identifies distinct genetic subtypes in extra-nodal natural killer/T-cell lymphoma. Leukemia 2022; 36:2064-2075. [PMID: 35697790 PMCID: PMC10499270 DOI: 10.1038/s41375-022-01623-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 05/22/2022] [Accepted: 05/27/2022] [Indexed: 02/05/2023]
Abstract
Extra-nodal NK/T-cell lymphoma, nasal type (ENKTCL) is a highly aggressive Epstein-Barr virus associated lymphoma, typically presenting in the nasal and paranasal areas. We assembled a large series of ENKTCL (n = 209) for comprehensive genomic analysis and correlative clinical study. The International Lymphoma Prognostic Index (IPI), site of disease, stage, lymphadenopathy, and hepatomegaly were associated with overall survival. Genetic analysis revealed frequent oncogenic activation of the JAK/STAT3 pathway and alterations in tumor suppressor genes (TSGs) and genes associated with epigenomic regulation. Integrated genomic analysis including recurrent mutations and genomic copy number alterations using consensus clustering identified seven distinct genetic clusters that were associated with different clinical outcomes, thus constituting previously unrecognized risk groups. The genetic profiles of ENTKCLs from Asian and Hispanic ethnic groups showed striking similarity, indicating shared pathogenetic mechanism and tumor evolution. Interestingly, we discovered a novel functional cooperation between activating STAT3 mutations and loss of the TSG, PRDM1, in promoting NK-cell growth and survival. This study provides a genetic roadmap for further analysis and facilitates investigation of actionable therapeutic opportunities in this aggressive lymphoma.
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Affiliation(s)
- Gehong Dong
- Department of Pathology, City of Hope National Medical Center, Duarte, CA, 91010, USA
- Department of Pathology, Beijing Tongren Hospital, Capital Medical University, 100730, Beijing, China
- Department of Pathology, Beijing Tiantan Hospital, Capital Medical University, 100070, Beijing, China
| | - Xuxiang Liu
- Department of Pathology, City of Hope National Medical Center, Duarte, CA, 91010, USA
| | - Lifu Wang
- Department of Pathology, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, 450003, China
| | - Wenjuan Yin
- Department of Pathology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, 310022, China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310018, China
| | - Alyssa Bouska
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Qiang Gong
- Department of Pathology, City of Hope National Medical Center, Duarte, CA, 91010, USA
| | - Kunal Shetty
- Department of Pathology, City of Hope National Medical Center, Duarte, CA, 91010, USA
| | - Lu Chen
- Department of Computational and Quantitative Medicine, City of Hope, Duarte, CA, 91010, USA
| | - Sunandini Sharma
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Jibin Zhang
- Department of Pathology, City of Hope National Medical Center, Duarte, CA, 91010, USA
| | - Carmen Lome-Maldonado
- Departamento de Patologia, Instituto Nacional de Cancerologia, 14080, Ciudad de México, Mexico
| | - Leticia Quintanilla-Martinez
- Institute of Pathology and Neuropathology, Eberhard Karls University of Tübingen and Comprehensive Cancer Center, University Hospital Tübingen, 72076, Tübingen, Germany
| | - Yuping Li
- Department of Pathology, City of Hope National Medical Center, Duarte, CA, 91010, USA
| | - Joo Y Song
- Department of Pathology, City of Hope National Medical Center, Duarte, CA, 91010, USA
| | - Wenyan Zhang
- Department of Pathology, West China Hospital, Chengdu, 610041, China
| | - Yunfei Shi
- Department of Pathology, City of Hope National Medical Center, Duarte, CA, 91010, USA
- Department of Pathology, Peking University Cancer Hospital and Institute, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), 100142, Beijing, China
| | - Jinhui Wang
- Integrative Genomics Core, City of Hope, Duarte, CA, 91010, USA
| | - Lingbo Kong
- Department of Pathology, City of Hope National Medical Center, Duarte, CA, 91010, USA
| | - Xiwei Wu
- Integrative Genomics Core, City of Hope, Duarte, CA, 91010, USA
| | - Jingwen Wang
- Department of Hematology, Beijing Tongren Hospital, Capital Medical University, 100730, Beijing, China
| | - Hong-Gang Liu
- Department of Pathology, Beijing Tiantan Hospital, Capital Medical University, 100070, Beijing, China
| | - Lingfei Kong
- Department of Pathology, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, 450003, China
| | - Wenyong Sun
- Department of Pathology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, 310022, China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310018, China
| | - Weiping Liu
- Department of Pathology, West China Hospital, Chengdu, 610041, China
| | - Lili Wang
- Department of Systems Biology, Beckman Research Institute, City of Hope, Monrovia, CA, 91016, USA
| | - Timothy W McKeithan
- Department of Pathology, City of Hope National Medical Center, Duarte, CA, 91010, USA
| | - Javeed Iqbal
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
| | - Wing C Chan
- Department of Pathology, City of Hope National Medical Center, Duarte, CA, 91010, USA.
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18
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Genetic and immunohistochemical profiling of NK/T-cell lymphomas reveals prognostically relevant BCOR-MYC association. Blood Adv 2022; 7:178-189. [PMID: 35882439 PMCID: PMC9837655 DOI: 10.1182/bloodadvances.2022007541] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/22/2022] [Accepted: 05/06/2022] [Indexed: 01/21/2023] Open
Abstract
Extranodal NK/T-cell lymphoma, nasal type (ENKTL) is an Epstein-Barr virus-positive, aggressive lymphoma with a heterogeneous cell of origin and variable clinical course. Several clinical prognostic indices have been proposed for ENKTL; however, there are few pathological biomarkers. This multi-institutional study sought to identify histologically assessable prognostic factors. We investigated mutation profiles by targeted next-generation sequencing (NGS) and immunohistochemical assessments of expression of MYC, Tyr705-phosphorylated (p-)STAT3, and CD30 in 71 ENKTL samples. The median age of the patients was 66 years (range, 6-100). The most frequent mutations were in STAT3 (27%), JAK3 (4%), KMT2D (19%), TP53 (13%), BCOR (10%), and DDX3X (7%). Immunohistochemistry (IHC) revealed that ENKTLs with STAT3 mutations exhibited higher expression of pSTAT3 and CD30. BCOR mutations were associated with increased MYC expression. Univariate analysis in the entire cohort showed that stage (II, III, or IV), BCOR mutations, TP53 mutations, and high MYC expression (defined as ≥40% positive neoplastic cells) were associated with reduced overall survival (OS). Multivariate modeling identified stage (II, III, or IV) and high MYC expression as independent adverse prognostic factors. In a subgroup analysis of patients treated with anthracycline (AC)-free chemotherapy and/or radiotherapy (RT) with curative intent, BCOR but not high MYC expression was an independent adverse prognostic factor. In conclusion, activating STAT3 mutations are common in ENKTLs and are associated with increased CD30 expression. MYC overexpression is, at least in part, associated with deleterious BCOR mutations, and this BCOR-MYC linkage may have prognostic significance, underscoring the potential utility of IHC for MYC in risk stratification of patients with ENKTL.
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Xu Y, Li P, Liu Y, Xin D, Lei W, Liang A, Han W, Qian W. Epi-immunotherapy for cancers: rationales of epi-drugs in combination with immunotherapy and advances in clinical trials. Cancer Commun (Lond) 2022; 42:493-516. [PMID: 35642676 PMCID: PMC9198339 DOI: 10.1002/cac2.12313] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 03/03/2022] [Accepted: 05/18/2022] [Indexed: 11/12/2022] Open
Abstract
Over the last two decades, several epi-drugs, immune checkpoint inhibitors (ICIs) and adoptive cell therapies have received clinical approval for use in certain types of cancer. However, monotherapy with epi-drugs or ICIs has shown limited efficacy in most cancer patients. Epigenetic agents have been shown to regulate the crosstalk between the tumor and host immunity to alleviate immune evasion, suggesting that epi-drugs can potentially synergize with immunotherapy. In this review, we discuss recent insights into the rationales of incorporating epigenetic therapy into immunotherapy, called epi-immunotherapy, and focus on an update of current clinical trials in both hematological and solid malignancies. Furthermore, we outline the future challenges and strategies in the field of cancer epi-immunotherapy.
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Affiliation(s)
- Yang Xu
- Department of Hematologythe Second Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouZhejiang310009P. R. China
- Zhejiang Provincial Key Laboratory for Cancer Molecular Cell BiologyLife Sciences InstituteZhejiang UniversityHangzhouZhejiang310058P. R. China
| | - Ping Li
- Department of HematologyTongji Hospital of Tongji UniversityShanghai200065P. R. China
| | - Yang Liu
- Department of Bio‐Therapeuticthe First Medical CentreChinese PLA General HospitalBeijing100853P. R. China
| | - Dijia Xin
- Department of Hematologythe Second Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouZhejiang310009P. R. China
- Zhejiang Provincial Key Laboratory for Cancer Molecular Cell BiologyLife Sciences InstituteZhejiang UniversityHangzhouZhejiang310058P. R. China
| | - Wen Lei
- Department of Hematologythe Second Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouZhejiang310009P. R. China
- Zhejiang Provincial Key Laboratory for Cancer Molecular Cell BiologyLife Sciences InstituteZhejiang UniversityHangzhouZhejiang310058P. R. China
| | - Aibin Liang
- Department of HematologyTongji Hospital of Tongji UniversityShanghai200065P. R. China
| | - Weidong Han
- Department of Bio‐Therapeuticthe First Medical CentreChinese PLA General HospitalBeijing100853P. R. China
| | - Wenbin Qian
- Department of Hematologythe Second Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouZhejiang310009P. R. China
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20
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Hue SSS, Ng SB, Wang S, Tan SY. Cellular Origins and Pathogenesis of Gastrointestinal NK- and T-Cell Lymphoproliferative Disorders. Cancers (Basel) 2022; 14:2483. [PMID: 35626087 PMCID: PMC9139583 DOI: 10.3390/cancers14102483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 05/08/2022] [Accepted: 05/13/2022] [Indexed: 11/25/2022] Open
Abstract
The intestinal immune system, which must ensure appropriate immune responses to both pathogens and commensal microflora, comprises innate lymphoid cells and various T-cell subsets, including intra-epithelial lymphocytes (IELs). An example of innate lymphoid cells is natural killer cells, which may be classified into tissue-resident, CD56bright NK-cells that serve a regulatory function and more mature, circulating CD56dim NK-cells with effector cytolytic properties. CD56bright NK-cells in the gastrointestinal tract give rise to indolent NK-cell enteropathy and lymphomatoid gastropathy, as well as the aggressive extranodal NK/T cell lymphoma, the latter following activation by EBV infection and neoplastic transformation. Conventional CD4+ TCRαβ+ and CD8αβ+ TCRαβ+ T-cells are located in the lamina propria and the intraepithelial compartment of intestinal mucosa as type 'a' IELs. They are the putative cells of origin for CD4+ and CD8+ indolent T-cell lymphoproliferative disorders of the gastrointestinal tract and intestinal T-cell lymphoma, NOS. In addition to such conventional T-cells, there are non-conventional T-cells in the intra-epithelial compartment that express CD8αα and innate lymphoid cells that lack TCRs. The central feature of type 'b' IELs is the expression of CD8αα homodimers, seen in monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), which primarily arises from both CD8αα+ TCRαβ+ and CD8αα+ TCRγδ+ IELs. EATL is the other epitheliotropic T-cell lymphoma in the GI tract, a subset of which arises from the expansion and reprograming of intracytoplasmic CD3+ innate lymphoid cells, driven by IL15 and mutations of the JAK-STAT pathway.
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Affiliation(s)
- Susan Swee-Shan Hue
- Department of Pathology, National University Hospital, Singapore 119074, Singapore; (S.S.-S.H.); (S.W.)
| | - Siok-Bian Ng
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore;
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore
| | - Shi Wang
- Department of Pathology, National University Hospital, Singapore 119074, Singapore; (S.S.-S.H.); (S.W.)
| | - Soo-Yong Tan
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore;
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21
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Yim J, Koh J, Kim S, Song SG, Bae JM, Yun H, Sung JY, Kim TM, Park SH, Jeon YK. Clinicopathologic and Genetic Features of Primary T-cell Lymphomas of the Central Nervous System: An Analysis of 11 Cases Using Targeted Gene Sequencing. Am J Surg Pathol 2022; 46:486-497. [PMID: 34980830 PMCID: PMC8923358 DOI: 10.1097/pas.0000000000001859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Primary central nervous system lymphoma (PCNSL) of peripheral T-cell lineage (T-PCNSL) is rare, and its genetic and clinicopathologic features remain unclear. Here, we present 11 cases of T-PCNSL in immunocompetent individuals from a single institute, focusing on their genetic alterations. Seven cases were subject to targeted panel sequencing covering 120 lymphoma-related genes. Nine of the eleven cases were classified as peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), of which one was of γδT-cell lineage. There was one case of anaplastic lymphoma kinase-positive anaplastic large cell lymphoma and another of extranodal natural killer (NK)/T-cell lymphoma (ENKTL) of αβT-cell lineage. The male to female ratio was 7 : 4 and the age ranged from 3 to 75 years (median, 61 y). Most patients presented with neurological deficits (n=10) and showed multifocal lesions (n=9) and deep brain structure involvement (n=9). Tumor cells were mostly small-to-medium, and T-cell monoclonality was detected in all nine evaluated cases. PTCL-NOS was CD4-positive (n=4), CD8-positive (n=3), mixed CD4-positive and CD8-positive (n=1), or CD4/CD8-double-negative (n=1, γδT-cell type). Cytotoxic molecule expression was observed in 4 (67%) of the 6 evaluated cases. Pathogenic alterations were found in 4 patients: one PTCL-NOS case had a frameshift mutation in KMT2C, another PTCL-NOS case harbored a truncating mutation in TET2, and another (γδT-cell-PTCL-NOS) harbored NRAS G12S and JAK3 M511I mutations, and homozygous deletions of CDKN2A and CDKN2B. The ENKTL (αβT-cell lineage) case harbored mutations in genes ARID1B, FAS, TP53, BCOR, KMT2C, POT1, and PRDM1. In conclusion, most of the T-PCNSL were PTCL-NOS, but sporadic cases of other subtypes including γδT-cell lymphoma, anaplastic lymphoma kinase-positive anaplastic large cell lymphoma, and ENKTL were also encountered. Immunophenotypic analysis, clonality test, and targeted gene sequencing along with clinicoradiologic evaluation, may be helpful for establishing the diagnosis of T-PCNSL. Moreover, this study demonstrates genetic alterations with potential diagnostic and therapeutic utility in T-PCNSL.
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MESH Headings
- Adolescent
- Adult
- Aged
- Anaplastic Lymphoma Kinase/metabolism
- Central Nervous System Neoplasms/genetics
- Central Nervous System Neoplasms/metabolism
- Central Nervous System Neoplasms/pathology
- Child
- Child, Preschool
- Female
- Humans
- Lymphoma, Extranodal NK-T-Cell/genetics
- Lymphoma, Extranodal NK-T-Cell/metabolism
- Lymphoma, Extranodal NK-T-Cell/pathology
- Lymphoma, Large-Cell, Anaplastic/genetics
- Lymphoma, Large-Cell, Anaplastic/metabolism
- Lymphoma, Large-Cell, Anaplastic/pathology
- Lymphoma, T-Cell, Peripheral/genetics
- Lymphoma, T-Cell, Peripheral/metabolism
- Lymphoma, T-Cell, Peripheral/pathology
- Male
- Middle Aged
- Young Adult
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Affiliation(s)
| | - Jiwon Koh
- Department of Pathology
- Center for Precision Medicine, Seoul National University Hospital
| | - Sehui Kim
- Department of Pathology
- Department of Pathology, Severance Hospital, Yonsei University College of Medicine
| | | | - Jeong Mo Bae
- Department of Pathology
- Center for Precision Medicine, Seoul National University Hospital
| | - Hongseok Yun
- Center for Precision Medicine, Seoul National University Hospital
| | - Ji-Youn Sung
- Department of Pathology, Kyung Hee University School of Medicine
| | - Tae Min Kim
- Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine
- Cancer Research Institute, Seoul National University, Seoul, Republic of Korea
| | | | - Yoon Kyung Jeon
- Department of Pathology
- Cancer Research Institute, Seoul National University, Seoul, Republic of Korea
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22
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Sun KH(M, Wong YT(H, Cheung KM(C, Yuen C(M, Chan YT(T, Lai WY(J, Chao C(D, Fan WS(K, Chow YK(K, Law MF, Tam HC(T. Update on Molecular Diagnosis in Extranodal NK/T-Cell Lymphoma and Its Role in the Era of Personalized Medicine. Diagnostics (Basel) 2022; 12:diagnostics12020409. [PMID: 35204500 PMCID: PMC8871212 DOI: 10.3390/diagnostics12020409] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 01/23/2022] [Accepted: 01/28/2022] [Indexed: 02/06/2023] Open
Abstract
Natural killer (NK)/T-cell lymphoma (NKTCL) is an aggressive malignancy with unique epidemiological, histological, molecular, and clinical characteristics. It occurs in two pathological forms, namely, extranodal NKTCL (ENKTCL) and aggressive NK leukemia, according to the latest World Health Organization (WHO) classification. Epstein–Barr virus (EBV) infection has long been proposed as the major etiology of lymphomagenesis. The adoption of high-throughput sequencing has allowed us to gain more insight into the molecular mechanisms of ENKTCL, which largely involve chromosome deletion and aberrations in Janus kinase (JAK)-signal transducer and activator of transcription (STAT), programmed cell death protein-1 (PD-1)/PD-ligand 1 (PD-L1) pathways, as well as mutations in tumor suppressor genes. The molecular findings could potentially influence the traditional chemoradiotherapy approach, which is known to be associated with significant toxicity. This article will review the latest molecular findings in NKTCL and recent advances in the field of molecular diagnosis in NKTCL. Issues of quality control and technical difficulties will also be discussed, along with future prospects in the molecular diagnosis and treatment of NKTCL.
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Affiliation(s)
- Ka-Hei (Murphy) Sun
- Division of Hematopathology, Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, Hong Kong; (K.-H.S.); (C.Y.)
| | | | - Ka-Man (Carmen) Cheung
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong; (K.-M.C.); (Y.-T.C.); (W.-Y.L.); (C.C.); (W.-S.F.); (Y.-K.C.); (H.-C.T.)
| | - Carmen (Michelle) Yuen
- Division of Hematopathology, Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, Hong Kong; (K.-H.S.); (C.Y.)
| | - Yun-Tat (Ted) Chan
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong; (K.-M.C.); (Y.-T.C.); (W.-Y.L.); (C.C.); (W.-S.F.); (Y.-K.C.); (H.-C.T.)
| | - Wing-Yan (Jennifer) Lai
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong; (K.-M.C.); (Y.-T.C.); (W.-Y.L.); (C.C.); (W.-S.F.); (Y.-K.C.); (H.-C.T.)
| | - Chun (David) Chao
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong; (K.-M.C.); (Y.-T.C.); (W.-Y.L.); (C.C.); (W.-S.F.); (Y.-K.C.); (H.-C.T.)
| | - Wing-Sum (Katie) Fan
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong; (K.-M.C.); (Y.-T.C.); (W.-Y.L.); (C.C.); (W.-S.F.); (Y.-K.C.); (H.-C.T.)
| | - Yuen-Kiu (Karen) Chow
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong; (K.-M.C.); (Y.-T.C.); (W.-Y.L.); (C.C.); (W.-S.F.); (Y.-K.C.); (H.-C.T.)
| | - Man-Fai Law
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong; (K.-M.C.); (Y.-T.C.); (W.-Y.L.); (C.C.); (W.-S.F.); (Y.-K.C.); (H.-C.T.)
- Correspondence:
| | - Ho-Chi (Tommy) Tam
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong; (K.-M.C.); (Y.-T.C.); (W.-Y.L.); (C.C.); (W.-S.F.); (Y.-K.C.); (H.-C.T.)
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23
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Mundy-Bosse BL, Weigel C, Wu YZ, Abdelbaky S, Youssef Y, Casas SB, Polley N, Ernst G, Young KA, McConnell KK, Nalin AP, Wu KG, Broughton M, Lordo MR, Altynova E, Hegewisch-Solloa E, Enriquez-Vera DY, Dueñas D, Barrionuevo C, Yu SC, Saleem A, Suarez CJ, Briercheck EL, Molina-Kirsch H, Loughran TP, Weichenhan D, Plass C, Reneau JC, Mace EM, Gamboa FV, Weinstock DM, Natkunam Y, Caligiuri MA, Mishra A, Porcu P, Baiocchi RA, Brammer JE, Freud AG, Oakes CC. Identification and targeting of the developmental blockade in extranodal natural killer/T cell lymphoma. Blood Cancer Discov 2022; 3:154-169. [PMID: 35247900 PMCID: PMC9414823 DOI: 10.1158/2643-3230.bcd-21-0098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 12/01/2021] [Accepted: 01/24/2022] [Indexed: 11/16/2022] Open
Abstract
Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive, rare lymphoma of natural killer (NK) cell origin with poor clinical outcomes. Here we used phenotypic and molecular profiling, including epigenetic analyses, to investigate how ENKTL ontogeny relates to normal NK-cell development. We demonstrate that neoplastic NK cells are stably, but reversibly, arrested at earlier stages of NK-cell maturation. Genes downregulated in the most epigenetic immature tumors were associated with polycomb silencing along with genomic gain and overexpression of EZH2. ENKTL cells exhibited genome-wide DNA hypermethylation. Tumor-specific DNA methylation gains were associated with polycomb-marked regions, involving extensive gene silencing and loss of transcription factor binding. To investigate therapeutic targeting, we treated novel patient-derived xenograft (PDX) models of ENKTL with the DNA hypomethylating agent, 5-azacytidine. Treatment led to reexpression of NK-cell developmental genes, phenotypic NK-cell differentiation, and prolongation of survival. These studies lay the foundation for epigenetic-directed therapy in ENKTL. SIGNIFICANCE Through epigenetic and transcriptomic analyses of ENKTL, a rare, aggressive malignancy, along with normal NK-cell developmental intermediates, we identified that extreme DNA hypermethylation targets genes required for NK-cell development. Disrupting this epigenetic blockade in novel PDX models led to ENKTL differentiation and improved survival. This article is highlighted in the In This Issue feature, p. 85.
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Affiliation(s)
- Bethany L. Mundy-Bosse
- Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio
- The Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio
- Corresponding Authors: Bethany L. Mundy-Bosse, The Ohio State University James Comprehensive Cancer Center, 882 Biomedical Research Tower, 460 West 12th Avenue, Columbus, OH 43210. Phone: 614-688-6564; E-mail: ; Aharon G. Freud, The Ohio State University James Comprehensive Cancer Center, 892 Biomedical Research Tower, 460 West 12th Avenue, Columbus, OH 43210. Phone: 614-293-7904; E-mail: ; and Christopher C. Oakes, The Ohio State University James Comprehensive Cancer Center, 455 OSU CCC/Wiseman Hall, 410 West 12th Avenue, Columbus, OH 43210. Phone: 614-685-9284; E-mail:
| | - Christoph Weigel
- Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio
- The Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio
| | - Yue-Zhong Wu
- Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio
- The Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio
| | - Salma Abdelbaky
- Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio
- The Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio
| | - Youssef Youssef
- Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio
| | - Susana Beceiro Casas
- Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio
| | - Nicholas Polley
- Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio
| | - Gabrielle Ernst
- The Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio
| | - Karen A. Young
- The Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio
| | - Kathleen K. McConnell
- The Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio
| | - Ansel P. Nalin
- Medical Scientist Training Program, The Ohio State University, Columbus, Ohio
| | - Kevin G. Wu
- The Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio
| | - Megan Broughton
- The Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio
| | - Matthew R. Lordo
- Medical Scientist Training Program, The Ohio State University, Columbus, Ohio
| | - Ekaterina Altynova
- The Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio
| | - Everardo Hegewisch-Solloa
- Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York
| | | | - Daniela Dueñas
- Instituto Nacional de Enfermedades Neoplasticas, Lima, Peru
| | | | - Shan-Chi Yu
- Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan
| | - Atif Saleem
- Department of Pathology, Stanford University School of Medicine, Stanford, California
| | - Carlos J. Suarez
- Department of Pathology, Stanford University School of Medicine, Stanford, California
| | - Edward L. Briercheck
- Department of Medicine, Division of Hematology and Medical Oncology, Fred Hutchinson Cancer Research Institute and the University of Washington, Seattle, Washington
| | | | - Thomas P. Loughran
- Division of Hematology, Department of Medicine, University of Virginia Cancer Center, Charlottesville, Virginia
| | - Dieter Weichenhan
- Division of Epigenomics, The German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Christoph Plass
- Division of Epigenomics, The German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - John C. Reneau
- Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio
- The Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio
| | - Emily M. Mace
- Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York
| | - Fabiola Valvert Gamboa
- Department of Medical Oncology, Liga Nacional Contra el Cáncer, Guatemala City, Guatemala
| | - David M. Weinstock
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Yasodha Natkunam
- Department of Pathology, Stanford University School of Medicine, Stanford, California
| | - Michael A. Caligiuri
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California
| | - Anjali Mishra
- Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Department of Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Pierluigi Porcu
- Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Department of Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Robert A. Baiocchi
- Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio
- The Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio
| | - Jonathan E. Brammer
- Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio
- The Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio
| | - Aharon G. Freud
- The Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio
- Department of Pathology, The Ohio State University, Columbus, Ohio
- Corresponding Authors: Bethany L. Mundy-Bosse, The Ohio State University James Comprehensive Cancer Center, 882 Biomedical Research Tower, 460 West 12th Avenue, Columbus, OH 43210. Phone: 614-688-6564; E-mail: ; Aharon G. Freud, The Ohio State University James Comprehensive Cancer Center, 892 Biomedical Research Tower, 460 West 12th Avenue, Columbus, OH 43210. Phone: 614-293-7904; E-mail: ; and Christopher C. Oakes, The Ohio State University James Comprehensive Cancer Center, 455 OSU CCC/Wiseman Hall, 410 West 12th Avenue, Columbus, OH 43210. Phone: 614-685-9284; E-mail:
| | - Christopher C. Oakes
- Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio
- The Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio
- Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio
- Corresponding Authors: Bethany L. Mundy-Bosse, The Ohio State University James Comprehensive Cancer Center, 882 Biomedical Research Tower, 460 West 12th Avenue, Columbus, OH 43210. Phone: 614-688-6564; E-mail: ; Aharon G. Freud, The Ohio State University James Comprehensive Cancer Center, 892 Biomedical Research Tower, 460 West 12th Avenue, Columbus, OH 43210. Phone: 614-293-7904; E-mail: ; and Christopher C. Oakes, The Ohio State University James Comprehensive Cancer Center, 455 OSU CCC/Wiseman Hall, 410 West 12th Avenue, Columbus, OH 43210. Phone: 614-685-9284; E-mail:
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The Pathologic and Genetic Characteristics of Extranodal NK/T-Cell Lymphoma. Life (Basel) 2022; 12:life12010073. [PMID: 35054466 PMCID: PMC8781285 DOI: 10.3390/life12010073] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 01/01/2022] [Accepted: 01/03/2022] [Indexed: 12/14/2022] Open
Abstract
Extranodal NK/T-cell lymphoma is a neoplasm of NK cells or cytotoxic T cells presenting in extranodal sites, most often in the nasal cavity. The typical immunophenotypes are cCD3+, sCD3-, CD4-, CD5-, CD8-, CD16-, and CD56+ with the expression of cytotoxic molecules. Tumor subsets express NK cell receptors, CD95/CD95L, CD30, MYC, and PDL1. Virtually all the tumor cells harbor the EBV genome, which plays a key role in lymphomagenesis as an epigenetic driver. EBV-encoded oncoproteins modulate the host-cell epigenetic machinery, reprogramming the viral and host epigenomes using host epigenetic modifiers. NGS analysis revealed the mutational landscape of ENKTL, predominantly involving the JAK-STAT pathway, epigenetic modifications, the RNA helicase family, the RAS/MAP kinase pathway, and tumor suppressors, which indicate an important role of these pathways and this group of genes in the lymphomagenesis of ENKTL. Recently, three molecular subtypes were proposed, the tumor-suppressor/immune-modulator (TSIM), MGA-BRDT (MB), and HDAC9-EP300-ARID1A (HEA) subtypes, and they are well-correlated with the cell of origin, EBV pattern, genomic alterations, and clinical outcomes. A future investigation into the function and interaction of discovered genes would be very helpful for better understanding the molecular pathogenesis of ENKTL and establishing better treatment strategies.
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Bigas A, Rodriguez-Sevilla JJ, Espinosa L, Gallardo F. Recent advances in T-cell lymphoid neoplasms. Exp Hematol 2021; 106:3-18. [PMID: 34879258 DOI: 10.1016/j.exphem.2021.12.191] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Revised: 11/29/2021] [Accepted: 12/02/2021] [Indexed: 12/14/2022]
Abstract
T Cells comprise many subtypes of specified lymphocytes, and their differentiation and function take place in different tissues. This cellular diversity is also observed in the multiple ways T-cell transformation gives rise to a variety of T-cell neoplasms. This review covers the main types of T-cell malignancies and their specific characteristics, emphasizing recent advances at the cellular and molecular levels as well as differences and commonalities among them.
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Affiliation(s)
- Anna Bigas
- Program in Cancer Research, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), CIBERONC, Barcelona, Spain; Institut Josep Carreras contra la Leucemia, Barcelona, Spain.
| | | | - Lluis Espinosa
- Program in Cancer Research, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), CIBERONC, Barcelona, Spain
| | - Fernando Gallardo
- Dermatology Department, Parc de Salut Mar-Hospital del Mar, Barcelona, Spain.
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26
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Primary breast CD20-positive extranodal NK/T cell lymphoma with stomach involvement: a case report and literature review. Diagn Pathol 2021; 16:103. [PMID: 34749754 PMCID: PMC8573996 DOI: 10.1186/s13000-021-01166-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Accepted: 10/27/2021] [Indexed: 12/01/2022] Open
Abstract
Background We present a unique case of primary breast CD20-positive extranodal NK/T cell lymphoma with stomach involvement in a young Chinese female patient. Case presentation The patient presented with a mass in her right breast that rapidly increased in size over approximately 2 months. Upper gastrointestinal endoscopy showed a giant serpentine ulcer in the stomach. Biopsy was performed, and microscopic inspection revealed that the fibrous tissue was diffusely involved by medium to large abnormal lymphocytes. The cytoplasm was low to moderate. The tumor cells had irregular nuclei and inconspicuous nucleoli. The lymphoid cells were strongly immunoreactive to CD20, CD3, CD4, CD56, TIA-1, EBER, and Ki-67 (90%). Epstein-Barr virus genomes were also found in tumor cells by in situ hybridization. A whole-body positron emission tomography (PET)-CT scan revealed intense FDG uptake in the right breast and greater curvature of the stomach. Monoclonal rearrangements of the T cell receptor (TCR-γ) and immunoglobulin heavy chain (IgH) were identified by genetic analysis. Whole-genome next-generation sequencing was performed, and up to 12 gene mutations, including a frameshift mutation in exon 4 of the BCOR (G97Rfs*87; 44.3%) gene and a base substitution mutation (Q61H 17.6%) in exon 3 of the KRAS gene, were detected. Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed using the database for annotation, visualization, and integrated discovery, which showed that rare primary breast CD20-positive extranodal NK/T cell lymphoma had a unique genetic background compared with diffuse large B cell lymphoma and extranodal NK/T cell lymphoma without CD20 expression. The patient received four cycles of the modified SMILE regimen. The second whole-body PET-CT scan revealed that the right breast mass was significantly smaller than before; additionally, FDG uptake in the stomach wall disappeared. Conclusions Systemic examination, extensive immunohistochemistry, and molecular profiling are essential for an accurate diagnosis. More similar cases are required to clarify the biological pathways and even the potential molecular mechanisms of rare lymphomas, which may help direct further treatment.
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27
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He X, Gao Y, Li Z, Huang H. Review on natural killer /T-cell lymphoma. Hematol Oncol 2021; 41:221-229. [PMID: 34731509 DOI: 10.1002/hon.2944] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 10/26/2021] [Indexed: 11/06/2022]
Abstract
Extranodal natural killer (NK)/T-cell lymphoma (ENKTL) is strongly associated with Epstein-Barr virus (EBV) and has a high prevalence in Asian and in Central and South America. About 85% of ENKTLs derive from NK cells and 15% from T-cells. Various factors have been implicated in the development of ENKTL. Molecular pathogenesis of NK/T-cell lymphomas include mutations of genes, involving in the Janus Kinase (JAK)/ signal transducer and activator of transcription (STAT) pathway, RNA helicase family, epigenetic regulation, and tumor suppression. The relationship between ENKTL and human leukocyte antigen (HLA) has been demonstrated. Radiotherapy (RT) plays a key role in the first-line treatment of early-stage. In stage III/IV diseases, non-anthracycline-regimens-containing L-asparaginase are recommended. Although clinical remission after L-asparaginase-based combination therapy has been achieved in the majority of patients with advanced-stage or relapsed/refractory(r/r) ENKL, the long-term overall survival is still poor. Recently, immunotherapy and new therapeutic targets have gained much attention. In this article, we discuss the pathogenesis, diagnosis, prognostic models and management options of ENKTL. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Xiaohua He
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China
| | - Yan Gao
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China
| | - Zhiming Li
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China
| | - Huiqiang Huang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China
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28
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Wang S, C Ordonez-Rubiano S, Dhiman A, Jiao G, Strohmier BP, Krusemark CJ, Dykhuizen EC. Polycomb group proteins in cancer: multifaceted functions and strategies for modulation. NAR Cancer 2021; 3:zcab039. [PMID: 34617019 PMCID: PMC8489530 DOI: 10.1093/narcan/zcab039] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 08/24/2021] [Accepted: 09/10/2021] [Indexed: 12/12/2022] Open
Abstract
Polycomb repressive complexes (PRCs) are a heterogenous collection of dozens, if not hundreds, of protein complexes composed of various combinations of subunits. PRCs are transcriptional repressors important for cell-type specificity during development, and as such, are commonly mis-regulated in cancer. PRCs are broadly characterized as PRC1 with histone ubiquitin ligase activity, or PRC2 with histone methyltransferase activity; however, the mechanism by which individual PRCs, particularly the highly diverse set of PRC1s, alter gene expression has not always been clear. Here we review the current understanding of how PRCs act, both individually and together, to establish and maintain gene repression, the biochemical contribution of individual PRC subunits, the mis-regulation of PRC function in different cancers, and the current strategies for modulating PRC activity. Increased mechanistic understanding of PRC function, as well as cancer-specific roles for individual PRC subunits, will uncover better targets and strategies for cancer therapies.
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Affiliation(s)
- Sijie Wang
- Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University and Purdue University Center for Cancer Research, 201 S. University St., West Lafayette, IN 47907 USA
| | - Sandra C Ordonez-Rubiano
- Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University and Purdue University Center for Cancer Research, 201 S. University St., West Lafayette, IN 47907 USA
| | - Alisha Dhiman
- Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University and Purdue University Center for Cancer Research, 201 S. University St., West Lafayette, IN 47907 USA
| | - Guanming Jiao
- Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University and Purdue University Center for Cancer Research, 201 S. University St., West Lafayette, IN 47907 USA
| | - Brayden P Strohmier
- Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University and Purdue University Center for Cancer Research, 201 S. University St., West Lafayette, IN 47907 USA
| | - Casey J Krusemark
- Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University and Purdue University Center for Cancer Research, 201 S. University St., West Lafayette, IN 47907 USA
| | - Emily C Dykhuizen
- Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University and Purdue University Center for Cancer Research, 201 S. University St., West Lafayette, IN 47907 USA
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29
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Dong G, Li Y, Lee L, Liu X, Shi Y, Liu X, Bouska A, Gong Q, Kong L, Wang J, Lou CH, McKeithan TW, Iqbal J, Chan WC. Genetic manipulation of primary human natural killer cells to investigate the functional and oncogenic roles of PRDM1. Haematologica 2021; 106:2427-2438. [PMID: 32732362 PMCID: PMC8409030 DOI: 10.3324/haematol.2020.254276] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Indexed: 12/29/2022] Open
Abstract
Extra-nodal natural killer (NK)/T-cell lymphoma, nasal type (ENKTCL) is a highly aggressive lymphoma, in which the tumor suppressor gene PRDM1 is frequently lost or inactivated. We employed two different CRISPR/Cas9 approaches to generate PRDM1-/- primary NK cells to study the role of this gene in NK-cell homeostasis. PRDM1-/- NK cells showed a marked increase in cloning efficiency, higher proliferation rate and less apoptosis compared with their wild-type counterparts. Gene expression profiling demonstrated a marked enrichment in pathways associated with proliferation, cell cycle, MYC, MYB and TCR/NK signaling in PRDM1-/- NK cells, but pathways associated with normal cellular functions including cytotoxic functions were downregulated, suggesting that the loss of PRDM1 shifted NK cells toward proliferation and survival rather than the performance of their normal functions. We were also able to further modify a PRDM1-deleted clone to introduce heterozygous deletions of common tumor suppressor genes in ENKTCL such as TP53, DDX3X, and PTPN6. We established an in vitro model to elucidate the major pathways through which PRDM1 mediates its homeostatic control of NK cells. This approach can be applied to the study of other relevant genetic lesions and oncogenic collaborations in lymphoma pathogenesis.
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Affiliation(s)
- Gehong Dong
- Department of Pathology, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Yuping Li
- Department of Pathology, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Logan Lee
- Department of Pathology, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Xuxiang Liu
- Department of Pathology, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Yunfei Shi
- Department of Pathology, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Xiaoqian Liu
- Department of Pathology, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Alyssa Bouska
- Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Qiang Gong
- Department of Pathology, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Lingbo Kong
- Department of Pathology, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Jinhui Wang
- Department of Mol and Cell Biol , City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Chih-Hong Lou
- The Gene Editing and Viral Vector Core, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Timothy W McKeithan
- Department of Pathology, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Javeed Iqbal
- Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Wing C Chan
- Department of Pathology, City of Hope National Medical Center, Duarte, CA 91010, USA
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30
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Vasella M, Wagner U, Fritz C, Seidl K, Giudici L, Exner GU, Moch H, Wild PJ, Bode-Lesniewska B. Novel RGAG1-BCOR gene fusion revealed in a somatic soft tissue sarcoma with a long follow-up. Virchows Arch 2021; 480:1107-1114. [PMID: 34331570 PMCID: PMC9033707 DOI: 10.1007/s00428-021-03160-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 07/03/2021] [Accepted: 07/07/2021] [Indexed: 12/24/2022]
Abstract
BCOR-rearranged sarcomas are rare and belong to the Ewing-like sarcomas (ELS). Their morphology and histopathological features make the diagnosis challenging. We present a case, initially diagnosed as an unusual extraskeletal myxoid chondrosarcoma (EMC). A 54-year-old male patient developed an asymptomatic swelling of the lower leg. Imaging showed a 9.5-cm large intramuscular soft tissue mass. Due to its morphological and immunohistochemical profile on biopsy, it was initially diagnosed as an EMC. The patient was treated by complete resection and adjuvant radiotherapy and remained free of tumor at 7 years follow-up. Using next-generation sequencing (NGS), we retrospectively identified RGAG1-BCOR gene fusion (confirmed by RT-PCR), which has not been described in somatic soft tissue tumors so far. This finding broadens the spectrum of partner genes in the BCOR-rearranged sarcomas in a tumor with a well-documented, long clinical follow-up.
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Affiliation(s)
- Mauro Vasella
- Department of Plastic Surgery and Hand Surgery, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland
| | - Ulrich Wagner
- Institute of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
| | - Christine Fritz
- Institute of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
| | - Kati Seidl
- Institute of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
| | - Luca Giudici
- Institute of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
| | | | - Holger Moch
- Institute of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
| | - Peter Johannes Wild
- Senckenberg Institute of Pathology, Goethe University Frankfurt, Frankfurt, Germany
| | - Beata Bode-Lesniewska
- Present Address: Pathology Institute Enge and University of Zurich, Zurich, Switzerland
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Epstein-Barr Virus-Associated T- and NK-Cell Lymphoproliferative Diseases: A Review of Clinical and Pathological Features. Cancers (Basel) 2021; 13:cancers13133315. [PMID: 34282778 PMCID: PMC8268319 DOI: 10.3390/cancers13133315] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 06/23/2021] [Accepted: 06/29/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary In most Epstein–Barr virus (EBV)-infected individuals, the virus establishes a lifelong latent infection with no specific clinical manifestation. However, EBV primary infection and secondary reactivation may cause various EBV-associated lymphoproliferative disorders (LPD), including hematologic malignancies. Among them, EBV-positive T/NK LPD are uncommon diseases defined by the proliferation of T- or NK-cells infected by EBV, more commonly encountered in Asians and Latin Americans. They encompass a spectrum of disorders ranging from indolent reactive lesions to malignant and aggressive diseases. Despite novel insights from high-throughput molecular studies, the pathogenesis of these disorders is not well understood, and EBV-positive T/NK LPD diagnoses remain challenging due to their rarity and considerable overlap. Indeed, this article discusses new insights into EBV-positive T/NK LPD and focuses on diagnosis challenges, describing the difficulties to clarify the borders between overlapping LPD subtypes. Abstract Epstein–Barr virus (EBV) is a ubiquitous virus detected in up to 95% of the general population. Most people are asymptomatic, while some may develop a wide range of EBV-associated lymphoproliferative disorders (LPD). Among them, EBV-positive T/NK LPD are uncommon diseases defined by the proliferation of T- or NK-cells infected by EBV. The 2017 World Health Organization (WHO) classification recognizes the following entities characterized by different outcomes: chronic active EBV infection of T- or NK-cell types (cutaneous and systemic forms), systemic EBV-positive T-cell lymphoma of childhood, EBV-positive aggressive NK-cell leukemia, extra nodal NK/T-cell lymphoma nasal type, and the new provisional entity known as primary EBV-positive nodal T/NK-cell lymphoma. In addition, EBV associated-hemophagocytic lymphohistiocytosis is part of EBV-positive T/NK LPD, but has not been included in the WHO classification due to its reactive nature. Despite novel insights from high-throughput molecular studies, EBV-positive NK/T-cell LPD diagnoses remain challenging, especially because of their rarity and overlap. Until now, an accurate EBV-positive NK/T LPD diagnosis has been based on its clinical presentation and course correlated with its histological features. This review aims to summarize clinical, pathological and molecular features of EBV-positive T/NK LPD subtypes and to provide an overview of new understandings regarding these rare disorders.
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Kyriazoglou A, Tourkantoni N, Liontos M, Zagouri F, Mahaira L, Papakosta A, Michali D, Patereli A, Stefanaki K, Tzotzola V, Skoura E, Baka M, Polychronopoulou S, Kattamis A, Dimitriadis E. A Case Series of BCOR Sarcomas With a New Splice Variant of BCOR/CCNB3 Fusion Gene. In Vivo 2021; 34:2947-2954. [PMID: 32871837 DOI: 10.21873/invivo.12125] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 06/22/2020] [Accepted: 06/24/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND/AIM Undifferentiated round cell sarcomas are a heterogeneous group of sarcomas. Identification of BCOR alterations, such as BCOR/CCNB3 and BCOR/MAML3 fusion genes and BCOR ITD has recently contributed in the precise diagnosis of these neoplasms, defining a new entity of the current classification of soft tissue and bone sarcomas. BCOR sarcomas share both morphological and genetic characteristics distinct from Ewing sarcomas. The scope of our study was to retrospectively identify BCOR sarcomas and find the correlations with the clinical outcome of these patients. PATIENTS AND METHODS Histopathology and immunohistochemistry of pediatric tumor samples were combined with molecular testing (PCR) and fluorescent in situ hybridization to find BCOR sarcomas. RESULTS We, herein, present our experience with BCOR sarcomas in a referral center of Greece. Moreover, we report in one case the detection of a variant BCOR/CCNB3 fusion not previously described. CONCLUSION We are the first to report a splice variant of BCOR/CCNB3 which reveals the central position of BCOR in the oncogenesis of these tumors, furthermore we highlight the importance of molecular diagnostics in Ewing-like sarcomas and discuss the current treatment options for this rare entity.
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Affiliation(s)
| | - Natalia Tourkantoni
- Division of Pediatric Oncology, First Department of Pediatrics, Aghia Sofia Children's Hospital, Athens, Greece
| | - Michalis Liontos
- Department of Clinical Therapeutics, General Hospital Alexandra, Athens, Greece
| | - Flora Zagouri
- Department of Clinical Therapeutics, General Hospital Alexandra, Athens, Greece
| | - Louisa Mahaira
- Department of Genetics, Aghios Savvas Hospital, Athens, Greece
| | | | - Dimitra Michali
- Department of Genetics, Aghios Savvas Hospital, Athens, Greece
| | - Amalia Patereli
- Department of Pathology, Aghia Sofia Children's Hospital, Athens, Greece
| | - Kalliopi Stefanaki
- Department of Pathology, Aghia Sofia Children's Hospital, Athens, Greece
| | - Vasiliki Tzotzola
- Department of Pediatric Oncology, Aghia Sofia Children's Hospital, Athens, Greece
| | | | - Margarita Baka
- Department of Pediatric Oncology, Panagiotis and Aglaia Kyriakou Children's Hospital, Athens, Greece
| | | | - Antonis Kattamis
- Division of Pediatric Oncology, First Department of Pediatrics, Aghia Sofia Children's Hospital, Athens, Greece
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BCOR gene alterations in hematological diseases. Blood 2021; 138:2455-2468. [PMID: 33945606 DOI: 10.1182/blood.2021010958] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 04/14/2021] [Indexed: 11/20/2022] Open
Abstract
The BCL6 co-repressor (BCOR) is a transcription factor involved in the control of embryogenesis, mesenchymal stem cells function, hematopoiesis and lymphoid development. Recurrent somatic clonal mutations of the BCOR gene and its homologue BCORL1 have been detected in several hematological malignancies and aplastic anemia. They are scattered across the whole gene length and mostly represent frameshifts (deletions, insertions), nonsense and missence mutations. These disruptive events lead to the loss of full-length BCOR protein and to the lack or low expression of a truncated form of the protein, both consistent with the tumor suppressor role of BCOR. BCOR and BCORL1 mutations are similar to those causing two rare X-linked diseases: the oculo-facio-cardio-dental (OFCD) and the Shukla-Vernon syndromes, respectively. Here, we focus on the structure and function of normal BCOR and BCORL1 in normal hematopoietic and lymphoid tissues and review the frequency and clinical significance of the mutations of these genes in malignant and non-malignant hematological diseases. Moreover, we discuss the importance of mouse models to better understand the role of Bcor loss, alone and combined with alterations of other genes (e.g. Dnmt3a and Tet2), in promoting hematological malignancies and in providing a useful platform for the development of new targeted therapies.
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Susan SSH, Ng SB, Wang S, Tan SY. Diagnostic approach to T- and NK-cell lymphoproliferative disorders in the gastrointestinal tract. Semin Diagn Pathol 2021; 38:21-30. [PMID: 34016481 DOI: 10.1053/j.semdp.2021.03.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 03/11/2021] [Accepted: 03/22/2021] [Indexed: 12/13/2022]
Abstract
Most gastrointestinal NK and T cell lymphomas are aggressive in behavior, although in recent years a subset of indolent lymphoproliferative disorders have been described, which must be distinguished from their more malignant mimics. Intestinal T-cell lymphomas may arise from intra-epithelial lymphocytes and display epitheliotropism, such as enteropathy-associated T-cell lymphoma and monomorphic epitheliotropic intestinal T-cell lymphoma. They are both aggressive in behavior but differ in their clinic-pathological features. On the other hand, intra-epithelial lymphocytes are not prominent in intestinal T-cell lymphoma, NOS, which is a diagnosis of exclusion and probably represents a heterogeneous group of entities. Indolent lymphoproliferative disorders of NK- and T-cells of both CD8 and CD4 subsets share a chronic, recurring clinical course but display differences from each other. CD8+ T-cell lymphoproliferative disorder of GI tract has a low proliferative fraction and does not progress nor undergo large cell transformation. Whilst NK-cell enteropathy runs an indolent clinical course, it may display a high proliferation fraction. On the other hand, CD4+ indolent T-cell lymphoproliferative disorder displays variable proliferation rates and may progress or transform after a number of years. In Asia and South America, it is not uncommon to see involvement of the gastrointestinal tract by EBV-associated extranodal NK/T cell lymphoma, nasal type, which must be distinguished from NK cell enteropathy and EBV-associated mucocutaneous ulcers.
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Affiliation(s)
- Swee-Shan Hue Susan
- Department of Pathology, National University Hospital Health Service, Singapore, Singapore; Department of Pathology, National University of Singapore Yong Loo Lin School of Medicine, Singapore, Singapore
| | - Siok-Bian Ng
- Department of Pathology, National University of Singapore Yong Loo Lin School of Medicine, Singapore, Singapore
| | - Shi Wang
- Department of Pathology, National University Hospital Health Service, Singapore, Singapore
| | - Soo-Yong Tan
- Department of Pathology, National University of Singapore Yong Loo Lin School of Medicine, Singapore, Singapore.
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EBV and the Pathogenesis of NK/T Cell Lymphoma. Cancers (Basel) 2021; 13:cancers13061414. [PMID: 33808787 PMCID: PMC8003370 DOI: 10.3390/cancers13061414] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 03/13/2021] [Accepted: 03/17/2021] [Indexed: 12/23/2022] Open
Abstract
Epstein-Barr virus (EBV) is a ubiquitous gamma herpes virus with tropism for B cells. EBV is linked to the pathogenesis of B cell, T cell and NK cell lymphoproliferations, with extranodal NK/T cell lymphoma, nasal type (ENKTCL) being the prototype of an EBV-driven lymphoma. ENKTCL is an aggressive neoplasm, particularly widespread in East Asia and the native population of Latin America, which suggests a strong genetic predisposition. The link between ENKTCL and different populations has been partially explored. EBV genome sequencing analysis recognized two types of strains and identified variants of the latent membrane protein 1 (LMP1), which revealed different oncogenic potential. In general, most ENKTCL patients carry EBV type A with LMP1 wild type, although the LMP1 variant with a 30 base pair deletion is also common, especially in the EBV type B, where it is necessary for oncogenic transformation. Contemporary high-throughput mutational analyses have discovered recurrent gene mutations leading to activation of the JAK-STAT pathway, and mutations in other genes such as BCOR, DDX3X and TP53. The genomic landscape in ENKTCL highlights mechanisms of lymphomagenesis, such as immune response evasion, secondary to alterations in signaling pathways or epigenetics that directly or indirectly interfere with oncogenes or tumor suppressor genes. This overview discusses the most important findings of EBV pathogenesis and genetics in ENKTCL.
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Sánchez-Romero C, Bologna-Molina R, Paes de Almeida O, Santos-Silva AR, Prado-Ribeiro AC, Brandão TB, Carlos R. Extranodal NK/T cell lymphoma, nasal type: An updated overview. Crit Rev Oncol Hematol 2021; 159:103237. [PMID: 33493634 DOI: 10.1016/j.critrevonc.2021.103237] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Revised: 06/09/2020] [Accepted: 01/16/2021] [Indexed: 02/07/2023] Open
Abstract
Extranodal NK/T-cell lymphoma, nasal type (ENKTCL-NT) is an aggressive malignancy associated with Epstein-Barr virus infection, with a geographic and racial predilection for some Asian and Latin American countries. ENKTCL-NT manifests as a necrotic process affecting nasal or upper aerodigestive structures and, rarely, extranasal sites such as skin, and the gastrointestinal tract. ENKTCL-NT was characterized by its poor prognosis irrespective of clinical stage and therapy. However, during the last two decades, advances in its clinicopathologic, genetic and molecular characterization have been achieved, as have changes in the chemotherapy regimens that, in combination with radiotherapy, are significantly improving the survival of these patients, especially in initial stages. For these reasons, we present an overview of the historical background of ENKTCL-NT along with an updated review of its potential etiological factors, clinicopathologic and molecular features, as well as its prognostic models, current treatment protocols, and future directions on potential promising therapeutic approaches.
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Affiliation(s)
- Celeste Sánchez-Romero
- Oral Pathology Section, Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas (UNICAMP), Av. Limeira 901, Piracicaba, Sao Paulo 1314‑903, Brazil; Department of Research, School of Dentistry, Universidad Juárez del Estado de Durango, Durango, Mexico.
| | - Ronell Bologna-Molina
- Molecular Pathology Area, Faculty of Dentistry, Universidad de la República, Montevideo, Uruguay; Department of Research, School of Dentistry, Universidad Juárez del Estado de Durango, Durango, Mexico
| | - Oslei Paes de Almeida
- Oral Pathology Section, Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas (UNICAMP), Av. Limeira 901, Piracicaba, Sao Paulo 1314‑903, Brazil
| | - Alan Roger Santos-Silva
- Oral Pathology Section, Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas (UNICAMP), Av. Limeira 901, Piracicaba, Sao Paulo 1314‑903, Brazil
| | - Ana Carolina Prado-Ribeiro
- Dental Oncology Service, Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
| | - Thaís Bianca Brandão
- Dental Oncology Service, Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
| | - Román Carlos
- Department of Pathology, Integra Cancer Center, Guatemala City, Guatemala
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Kang JH, Lee SH, Lee J, Choi M, Cho J, Kim SJ, Kim WS, Ko YH, Yoo HY. The mutation of BCOR is highly recurrent and oncogenic in mature T-cell lymphoma. BMC Cancer 2021; 21:82. [PMID: 33468080 PMCID: PMC7816311 DOI: 10.1186/s12885-021-07806-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 01/11/2021] [Indexed: 01/08/2023] Open
Abstract
Background BCOR acts as a corepressor of BCL6, a potent oncogenic protein in cancers of the lymphoid lineage. We have found the recurrent somatic mutation of BCOR occurred in mature T-cell lymphoma (TCL). The role of BCOR mutation in lymphoid malignancies is unknown. Methods Lymphoma patient samples were analyzed to identify missense mutations in BCOR using Sanger sequencing. Transfection, RNA interference, immunoprecipitation, western blotting, cell proliferation, cytokine assays and quantitative real-time PCR were employed to determine the functional relevance of the novel K607E mutation in BCOR. The significant transcriptional changes were analyzed by performing DNA microarray profiling in cells expressing BCOR K607E mutant. Results One hundred thirty-seven lymphoma patient samples were analyzed to identify K607E mutation of the BCOR gene. The BCOR K607E mutation was identified in 15 of 47 NK/T cell lymphoma cases (31.9%), 2 of 18 angioimmunoblastic T-cell lymphoma cases (11.1%), 10 of 30 peripheral T-cell lymphoma, not otherwise specified cases (33.3%), and 13 of 42 diffuse large B-cell lymphoma cases (30.9%). Molecular analysis of BCOR K607E mutation revealed that compared to the wild-type BCOR, the mutant BCOR bound to the BCL6, PCGF1, and RING1B proteins with lesser affinity. Ectopic expression of BCOR K607E mutant significantly enhanced cell proliferation, AKT phosphorylation and the expression of interleukin-2 (IL-2) with up-regulated expression of HOX and S100 protein genes in T cells. BCOR silencing also significantly enhanced cell proliferation, AKT phosphorylation, and IL-2 production. Conclusions Functional analyses indicated that K607E mutation of BCOR is oncogenic in nature and can serve as a genetic marker of T-cell lymphoma. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-07806-8.
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Affiliation(s)
- Jin Hyun Kang
- Clinical Research Institute, Research Institute for Future Medicine, Samsung Medical Center, Seoul, South Korea
| | - Seung Ho Lee
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, 81 Ilwon-Ro, Gangnam-Gu, Seoul, 06351, South Korea
| | - Jawon Lee
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea
| | - Murim Choi
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea
| | - Junhun Cho
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Ilwon-Ro, Gangnam-Gu, Seoul, 06351, South Korea
| | - Seok Jin Kim
- Samsung Biomedical Research Institute, Research Institute for Future Medicine, Samsung Medical Center, Seoul, South Korea.,Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Won Seog Kim
- Samsung Biomedical Research Institute, Research Institute for Future Medicine, Samsung Medical Center, Seoul, South Korea.,Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Young Hyeh Ko
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Ilwon-Ro, Gangnam-Gu, Seoul, 06351, South Korea. .,Samsung Biomedical Research Institute, Research Institute for Future Medicine, Samsung Medical Center, Seoul, South Korea.
| | - Hae Yong Yoo
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, 81 Ilwon-Ro, Gangnam-Gu, Seoul, 06351, South Korea. .,Samsung Biomedical Research Institute, Research Institute for Future Medicine, Samsung Medical Center, Seoul, South Korea.
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Kaito S, Iwama A. Pathogenic Impacts of Dysregulated Polycomb Repressive Complex Function in Hematological Malignancies. Int J Mol Sci 2020; 22:ijms22010074. [PMID: 33374737 PMCID: PMC7793497 DOI: 10.3390/ijms22010074] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 12/17/2020] [Accepted: 12/19/2020] [Indexed: 02/06/2023] Open
Abstract
Polycomb repressive complexes (PRCs) are epigenetic regulators that mediate repressive histone modifications. PRCs play a pivotal role in the maintenance of hematopoietic stem cells through repression of target genes involved in cell proliferation and differentiation. Next-generation sequencing technologies have revealed that various hematologic malignancies harbor mutations in PRC2 genes, such as EZH2, EED, and SUZ12, and PRC1.1 genes, such as BCOR and BCORL1. Except for the activating EZH2 mutations detected in lymphoma, most of these mutations compromise PRC function and are frequently associated with resistance to chemotherapeutic agents and poor prognosis. Recent studies have shown that mutations in PRC genes are druggable targets. Several PRC2 inhibitors, including EZH2-specific inhibitors and EZH1 and EZH2 dual inhibitors have shown therapeutic efficacy for tumors with and without activating EZH2 mutations. Moreover, EZH2 loss-of-function mutations appear to be attractive therapeutic targets for implementing the concept of synthetic lethality. Further understanding of the epigenetic dysregulation associated with PRCs in hematological malignancies should improve treatment outcomes.
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Affiliation(s)
| | - Atsushi Iwama
- Correspondence: ; Tel.: +81-3-6409-2181; Fax: +81-3-6409-2182
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Aggressive NK Cell Leukemia: Current State of the Art. Cancers (Basel) 2020; 12:cancers12102900. [PMID: 33050313 PMCID: PMC7600035 DOI: 10.3390/cancers12102900] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 09/18/2020] [Accepted: 09/29/2020] [Indexed: 12/16/2022] Open
Abstract
Simple Summary Aggressive natural killer cell leukemia (ANKL) is a rare, lethal disease that presents many diagnostic and therapeutic challenges. Recent studies have shed new light on the salient features of its molecular pathogenesis and provided further insight into the clinicopathologic spectrum of this disease. This review presents a state-of-the-art overview of ANKL, spanning its historical evolution as a distinct entity, pathobiology, and potential therapeutic vulnerabilities. Abstract Aggressive natural killer (NK) cell leukemia (ANKL) is a rare disease with a grave prognosis. Patients commonly present acutely with fever, constitutional symptoms, hepatosplenomegaly, and often disseminated intravascular coagulation or hemophagocytic syndrome. This acute clinical presentation and the variable pathologic and immunophenotypic features of ANKL overlap with other diagnostic entities, making it challenging to establish a timely and accurate diagnosis of ANKL. Since its original recognition in 1986, substantial progress in understanding this disease using traditional pathologic approaches has improved diagnostic accuracy. This progress, in turn, has facilitated the performance of recent high-throughput studies that have yielded insights into pathogenesis. Molecular abnormalities that occur in ANKL can be divided into three major groups: JAK/STAT pathway activation, epigenetic dysregulation, and impairment of TP53 and DNA repair. These high-throughput data also have provided potential therapeutic targets that promise to improve therapy and outcomes for patients with ANKL. In this review, we provide a historical context of the conception and evolution of ANKL as a disease entity, we highlight advances in diagnostic criteria to recognize this disease, and we review recent understanding of pathogenesis as well as biomarker discoveries that are providing groundwork for innovative therapies.
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Feng J, Ouyang Y, Xu D, He Q, Liu D, Fan X, Xu P, Mo Y. Genetic variants in MIR17HG affect the susceptibility and prognosis of glioma in a Chinese Han population. BMC Cancer 2020; 20:976. [PMID: 33036577 PMCID: PMC7547478 DOI: 10.1186/s12885-020-07417-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Accepted: 09/15/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND lncRNA MIR17HG was upregulated in glioma, and participated in promoting proliferation, migration and invasion of glioma. However, the role of MIR17HG polymorphisms in the occurrence and prognosis of glioma is still unclear. METHODS In the study, 592 glioma patients and 502 control subjects were recruited. Agena MassARRAY platform was used to detect the genotype of MIR17HG polymorphisms. Logistic regression analysis was used to evaluate the relationship between MIR17HG single nucleotide polymorphisms (SNPs) and glioma risk by odds ratio (OR) and 95% confidence intervals (CIs). Kaplan-Meier curves, Cox hazards models were performed for assessing the role of these SNPs in glioma prognosis by hazard ratios (HR) and 95% CIs. RESULTS We found that rs7318578 (OR = 2.25, p = 3.18 × 10- 5) was significantly associated with glioma susceptibility in the overall participants. In the subgroup with age < 40 years, rs17735387 (OR = 1.53, p = 9.05 × 10- 3) and rs7336610 (OR = 1.35, p = 0.016) were related to the higher glioma susceptibility. More importantly, rs17735387 (HR = 0.82, log-rank p = 0.026) were associated with the longer survival of glioma patients. The GA genotype of rs17735387 had a better overall survival (HR = 0.75, log-rank p = 0.013) and progression free survival (HR = 0.73, log-rank p = 0.032) in patients with I-II glioma. We also found that rs72640334 was related to the poor prognosis (HR = 1.49, Log-rank p = 0.035) in female patients. In the subgroup of patients with age ≥ 40 years, rs17735387 was associated with a better prognosis (HR = 0.036, Log-rank p = 0.002). CONCLUSION Our study firstly reported that MIR17HG rs7318578 was a risk factor for glioma susceptibility and rs17735387 was associated with the longer survival of glioma among Chinese Han population, which might help to enhance the understanding of MIR17HG gene in gliomagenesis. In subsequent studies, we will continue to collect samples and follow up to further validate our findings and further explore the function of these MIR17HG SNPs in glioma in a larger sample size.
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Affiliation(s)
- Jigao Feng
- Department of Neurosurgery, the Second Affiliated Hospital of Hainan Medical University, #48 Baishuitang Road, Haikou, 570311, Hainan, China
| | - Yibin Ouyang
- Department of Neurosurgery, the Second Affiliated Hospital of Hainan Medical University, #48 Baishuitang Road, Haikou, 570311, Hainan, China
| | - Dedong Xu
- Department of Neurosurgery, the Second Affiliated Hospital of Hainan Medical University, #48 Baishuitang Road, Haikou, 570311, Hainan, China
| | - Qinglong He
- Department of Neurosurgery, the Second Affiliated Hospital of Hainan Medical University, #48 Baishuitang Road, Haikou, 570311, Hainan, China
| | - Dayuan Liu
- Department of Neurosurgery, the Second Affiliated Hospital of Hainan Medical University, #48 Baishuitang Road, Haikou, 570311, Hainan, China
| | - Xudong Fan
- Department of Neurosurgery, the Second Affiliated Hospital of Hainan Medical University, #48 Baishuitang Road, Haikou, 570311, Hainan, China
| | - Pengxiang Xu
- Department of Neurosurgery, the Second Affiliated Hospital of Hainan Medical University, #48 Baishuitang Road, Haikou, 570311, Hainan, China
| | - Yehe Mo
- Department of Neurosurgery, the Second Affiliated Hospital of Hainan Medical University, #48 Baishuitang Road, Haikou, 570311, Hainan, China.
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Epstein-Barr virus-associated gastric cancer: A distinct subtype. Cancer Lett 2020; 495:191-199. [PMID: 32979463 DOI: 10.1016/j.canlet.2020.09.019] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 08/28/2020] [Accepted: 09/21/2020] [Indexed: 12/11/2022]
Abstract
Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) is a common malignant tumor associated with EBV infection. The molecular classification of gastric carcinoma indicates that EBVaGC is a distinct subtype in terms of oncogenesis and molecular features. Viral proteins, Bam-HI-A rightward transcripts (BART) miRNAs, and Bam-HI A rightward frame 1 (BARF1) promote oncogenesis after EBV infection via the induction of methylation, regulation of host gene expression, and malignant transformation. Together with abnormal mutations and amplification of the host genome as driving factors, interactions between the EBV genome and host genome accelerate carcinogenesis. The molecular profile of EBVaGC is that of EBV driving DNA hypermethylation, frequent phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations, and the overexpression of Janus kinase 2 (JAK2), programmed death ligand-1 (PD-L1), and PD-L2. Clinically, the frequency of lymph node metastasis is lower, and the prognosis is better for EBVaGC than EBV-negative gastric cancer (EBVnGC). Pathologically, EBVaGC is a gastric adenocarcinoma with lymphoid stroma. This review interprets how the EBV genome is involved in the oncogenesis of gastric cancer and describes the molecular and clinicopathological features of EBVaGC.
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KDM2B in polycomb repressive complex 1.1 functions as a tumor suppressor in the initiation of T-cell leukemogenesis. Blood Adv 2020; 3:2537-2549. [PMID: 31471323 DOI: 10.1182/bloodadvances.2018028522] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2018] [Accepted: 06/21/2019] [Indexed: 12/11/2022] Open
Abstract
KDM2B together with RING1B, PCGF1, and BCOR or BCORL1 comprise polycomb repressive complex 1.1 (PRC1.1), a noncanonical PRC1 that catalyzes H2AK119ub1. It binds to nonmethylated CpG islands through its zinc finger-CxxC DNA binding domain and recruits the complex to target gene loci. Recent studies identified the loss of function mutations in the PRC1.1 gene, BCOR and BCORL1 in human T-cell acute lymphoblastic leukemia (T-ALL). We previously reported that Bcor insufficiency induces T-ALL in mice, supporting a tumor suppressor role for BCOR. However, the function of BCOR responsible for tumor suppression, either its corepressor function for BCL6 or that as a component of PRC1.1, remains unclear. We herein examined mice specifically lacking the zinc finger-CxxC domain of KDM2B in hematopoietic cells. Similar to Bcor-deficient mice, Kdm2b-deficient mice developed lethal T-ALL mostly in a NOTCH1-dependent manner. A chromatin immunoprecipitation sequence analysis of thymocytes revealed the binding of KDM2B at promoter regions, at which BCOR and EZH2 colocalized. KDM2B target genes markedly overlapped with those of NOTCH1 in human T-ALL cells, suggesting that noncanonical PRC1.1 antagonizes NOTCH1-mediated gene activation. KDM2B target genes were expressed at higher levels than the others and were marked with high levels of H2AK119ub1 and H3K4me3, but low levels of H3K27me3, suggesting that KDM2B target genes are transcriptionally active or primed for activation. These results indicate that PRC1.1 plays a key role in restricting excessive transcriptional activation by active NOTCH1, thereby acting as a tumor suppressor in the initiation of T-cell leukemogenesis.
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Li Q, Zhang W, Li J, Xiong J, Liu J, Chen T, Wen Q, Zeng Y, Gao L, Gao L, Zhang C, Kong P, Peng X, Liu Y, Zhang X, Rao J. Plasma circulating tumor DNA assessment reveals KMT2D as a potential poor prognostic factor in extranodal NK/T-cell lymphoma. Biomark Res 2020; 8:27. [PMID: 32695399 PMCID: PMC7366898 DOI: 10.1186/s40364-020-00205-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 07/06/2020] [Indexed: 12/20/2022] Open
Abstract
Background The early detection of tumors upon initial diagnosis or during routine surveillance is important for improving survival outcomes. Here, we investigated the feasibility and clinical significance of circulating tumor DNA (ctDNA) detection for Extranodal NK/T-cell lymphoma, nasal type (ENTKL). Methods The plasma ctDNA assessment was based on blood specimens collected from 65 newly diagnosed patients with ENKTL in the hematology medical center of Xinqiao Hospital. Longitudinal samples collected under chemotherapy were also included. The gene mutation spectrum of ENKTL was analyzed via next generation sequencing. Results We found that the most frequently mutated genes were KMT2D (23.1%), APC (12.3%), ATM (10.8%), ASXL3 (9.2%), JAK3 (9.2%), SETD2 (9.2%), TP53 (9.2%) and NOTCH1 (7.7%). The mutation allele frequencies of ATM and JAK3 were significantly correlated with the disease stage, and mutated KMT2D, ASXL3 and JAK3 were positively correlated with the metabolic tumor burden of the patients. Compared with the tumor tissue, ctDNA profiling showed good concordance (93.75%). Serial ctDNA analysis showed that treatment with chemotherapy could decrease the number and mutation allele frequencies of the genes. Compared with PET/CT, ctDNA has more advantages in tracking residual disease in patients. In addition, patients with mutated KMT2D had higher expression compared with those with wild type, and mutated KMT2D predicted poor prognosis. Conclusion Our results unveil the mutation spectrum of ENKTL patients' plasma, which can be used to monitor the disease status of the patients exactly, and KMT2D is the most frequently mutated gene with prognosis prediction value. The application of ctDNA sequencing can provide precision treatment strategies for patients. Trial registration This study is registered with chictr.org (ChiCTR1800014813, registered 7 February, 2018-Retrospectively registered).
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Affiliation(s)
- Qiong Li
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China.,State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400037 China
| | - Wei Zhang
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China.,State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400037 China
| | - Jiali Li
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China.,State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400037 China
| | - Jingkang Xiong
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China.,State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400037 China
| | - Jia Liu
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China.,State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400037 China
| | - Ting Chen
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China.,State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400037 China
| | - Qin Wen
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China.,State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400037 China
| | - Yunjing Zeng
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China.,State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400037 China
| | - Li Gao
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China.,State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400037 China
| | - Lei Gao
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China.,State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400037 China
| | - Cheng Zhang
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China.,State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400037 China
| | - Peiyan Kong
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China.,State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400037 China
| | - Xiangui Peng
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China.,State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400037 China
| | - Yao Liu
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China.,State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400037 China
| | - Xi Zhang
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China.,State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400037 China
| | - Jun Rao
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China.,State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400037 China
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44
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Montes-Mojarro IA, Chen BJ, Ramirez-Ibarguen AF, Quezada-Fiallos CM, Pérez-Báez WB, Dueñas D, Casavilca-Zambrano S, Ortiz-Mayor M, Rojas-Bilbao E, García-Rivello H, Metrebian MF, Narbaitz M, Barrionuevo C, Lome-Maldonado C, Bonzheim I, Fend F, Steinhilber J, Quintanilla-Martinez L. Mutational profile and EBV strains of extranodal NK/T-cell lymphoma, nasal type in Latin America. Mod Pathol 2020; 33:781-791. [PMID: 31822801 DOI: 10.1038/s41379-019-0415-5] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 10/19/2019] [Accepted: 10/22/2019] [Indexed: 11/09/2022]
Abstract
Extranodal NK/T-cell lymphoma (ENKTL) is an Epstein-Barr virus (EBV) associated lymphoma, prevalent in Asia and Latin America. Studies in Asian cohorts have identified some recurrent gene mutations in ENKTL; however, the mutational landscape of ENKTL in Latin America is unknown. In this study, we investigated the mutational profile and EBV strains of 71 ENKTL cases from Latin America (42 from Mexico, 17 from Peru, and 12 from Argentina) and compared it with Asian cohorts. The mutational analysis was performed by next generation sequencing (NGS) using an Ion AmpliSeq™ custom panel covering for the most frequently mutated genes identified in ENKTL. STAT3 was the most frequent mutated gene (16 cases: 23%), followed by MSN (10 cases; 14%), BCOR (9 cases; 13%), DDX3X (6 cases; 8%), TP53 (6 cases; 8%), MGA (3 cases; 4%), JAK3 (2 cases; 3%), and STAT5B (1 case; 1%). Mutations in STAT3, BCOR, and DDX3X were nearly mutually exclusive, suggesting different molecular pathways involved in the pathogenesis of ENKTL; whereas mutations in MGA, MSN, and TP53 were concomitant with other mutations. Most cases (75%) carried Type A EBV without the 30-bp LMP1 gene deletion. The overall survival was significantly associated with serum LDH level, Eastern Cooperative Oncology Group (ECOG) performance status, International Prognostic Index (IPI) score, and therapy (p < 0.05), but not associated with any mutation, EBV strain or deletion in EBV LMP1 gene. In conclusion, mutational analysis of ENKTL from Latin America reveals frequent gene mutations leading to activation of the JAK-STAT pathway (25%), mostly STAT3. Compared to Asian cohorts, BCOR, DDX3X and TP53 mutations were also identified but with different frequencies. None of these mutations were associated with prognosis.
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Affiliation(s)
- Ivonne A Montes-Mojarro
- Institute of Pathology and Neuropathology, Eberhard Karls University of Tübingen and Comprehensive Cancer Center, Tübingen University Hospital, Tübingen, Germany
| | - Bo-Jung Chen
- Institute of Pathology and Neuropathology, Eberhard Karls University of Tübingen and Comprehensive Cancer Center, Tübingen University Hospital, Tübingen, Germany.,Department of Pathology, Shuang-Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
| | | | | | - Wendy B Pérez-Báez
- Department of Pathology, Instituto Nacional de Cancerología, Mexico City, Mexico
| | - Daniela Dueñas
- Department of Pathology, Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru
| | | | - Marcela Ortiz-Mayor
- Department of Pathology, Hospital Ángel C. Padilla, San Miguel Tucumán, Argentina
| | - Erica Rojas-Bilbao
- Department of Pathology, Instituto de Oncología Ángel H. Roffo, Buenos Aires, Argentina
| | | | - Maria F Metrebian
- Department of Pathology, Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina, Buenos Aires, Argentina
| | - Marina Narbaitz
- Department of Pathology, Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina, Buenos Aires, Argentina
| | - Carlos Barrionuevo
- Department of Pathology, Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru
| | | | - Irina Bonzheim
- Institute of Pathology and Neuropathology, Eberhard Karls University of Tübingen and Comprehensive Cancer Center, Tübingen University Hospital, Tübingen, Germany
| | - Falko Fend
- Institute of Pathology and Neuropathology, Eberhard Karls University of Tübingen and Comprehensive Cancer Center, Tübingen University Hospital, Tübingen, Germany
| | - Julia Steinhilber
- Institute of Pathology and Neuropathology, Eberhard Karls University of Tübingen and Comprehensive Cancer Center, Tübingen University Hospital, Tübingen, Germany
| | - Leticia Quintanilla-Martinez
- Institute of Pathology and Neuropathology, Eberhard Karls University of Tübingen and Comprehensive Cancer Center, Tübingen University Hospital, Tübingen, Germany.
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45
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Küçük C, Wang J, Xiang Y, You H. Epigenetic aberrations in natural killer/T-cell lymphoma: diagnostic, prognostic and therapeutic implications. Ther Adv Med Oncol 2020; 12:1758835919900856. [PMID: 32127923 PMCID: PMC7036507 DOI: 10.1177/1758835919900856] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Accepted: 12/19/2019] [Indexed: 12/11/2022] Open
Abstract
Natural killer/T-cell lymphoma (NKTCL) is an aggressive malignancy that usually presents in the upper aerodigestive tract. This malignancy shows substantial geographic variability in incidence, and is characterized by Epstein-Barr virus (EBV) infections. Epigenetic aberrations may dysregulate the expression of genes involved in different hallmarks of cancer. A growing body of evidence underscores the importance of epigenetic aberrations in the pathogenesis of NKTCL. Promoter hypermethylation is a common epigenetic mechanism for the inactivation of tumour suppressor genes. Several epigenetically silenced tumour suppressor candidates (e.g. PRDM1, BIM) were identified in this aggressive cancer using locus-specific and genome-wide promoter methylation analyses. Importantly, genes involved in epigenetic modifications were identified to be mutated (e.g. KMT2D) or methylated (e.g. TET2) in NKTCL patients, which may contribute to pathogenesis through global alterations in chromatin states. Cancer-associated microRNAs, some of which are expressed by EBV, and long noncoding RNAs have been observed to be dysregulated in NKTCL. This review focuses on studies investigating epigenetic aberrations in NKTCL to bolster our overall understanding of the role of these abnormalities in disease pathobiology. We also discuss the potential of these epigenetic aberrations to improve diagnosis and prognosis as well as reveal novel targets of therapy for NKTCL.
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Affiliation(s)
- Can Küçük
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Junli Wang
- Department of Reproduction and Genetics, the Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, China
| | - Ying Xiang
- Division of Hematology and Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China
| | - Hua You
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, No.78 Heng-Zhi-Gang Road, Yue Xiu District, Guangzhou 510095, China
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46
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Lempiäinen JK, Manjur ABMK, Malinen M, Ketola K, Niskanen EA, Palvimo JJ. BCOR-coupled H2A monoubiquitination represses a subset of androgen receptor target genes regulating prostate cancer proliferation. Oncogene 2020; 39:2391-2407. [PMID: 31925334 DOI: 10.1038/s41388-020-1153-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 12/17/2019] [Accepted: 12/31/2019] [Indexed: 12/20/2022]
Abstract
We have identified BCL6 corepressor (BCOR) as a hormone-dependent interaction partner of androgen receptor (AR), a key transcription factor in the development of normal and cancerous prostate. BCOR is often mutated in cancers and hematological diseases and as a component of a non-canonical polycomb repressive complex 1 (ncPRC1.1) required for arranging many facets of cellular differentiation. However, its role in androgen signaling or prostate cancer cells remains unknown. Here, our genome-wide analyses reveal that BCOR is recruited in an androgen-dependent fashion to majority of AR-binding chromatin sites in castration-resistant prostate cancer (CRPC) cells. Interestingly, depletion of BCOR has a significant effect on the expression of androgen-repressed genes linked to regulation of cell proliferation, differentiation and development. At many of these genes, such as HOX genes, the depletion leads to a decrease in H2A K119 monoubiquitination and an increase in mRNA expression. Consistently, BCOR depletion impairs the proliferation and viability of CRPC cells, inducing their apoptosis. Collectively, our data indicate a key role for the BCOR-ncPRC1.1 complex in the corepression of an important subset of AR target genes and the regulation of prostate cancer cell proliferation.
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Affiliation(s)
| | | | - Marjo Malinen
- Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.,Department of Environmental and Biological Sciences, University of Eastern Finland, Joensuu, Finland
| | - Kirsi Ketola
- Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
| | - Einari A Niskanen
- Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
| | - Jorma J Palvimo
- Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
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47
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Soderquist CR, Bhagat G. Gastrointestinal T- and NK-cell lymphomas and indolent lymphoproliferative disorders. Semin Diagn Pathol 2020; 37:11-23. [DOI: 10.1053/j.semdp.2019.08.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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48
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Shanmugam V, Kim AS. Lymphomas. Genomic Med 2020. [DOI: 10.1007/978-3-030-22922-1_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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49
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Murata T, Okuno Y, Sato Y, Watanabe T, Kimura H. Oncogenesis of CAEBV revealed: Intragenic deletions in the viral genome and leaky expression of lytic genes. Rev Med Virol 2019; 30:e2095. [PMID: 31845495 DOI: 10.1002/rmv.2095] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 11/26/2019] [Accepted: 11/27/2019] [Indexed: 12/19/2022]
Abstract
Epstein-Barr virus (EBV) is a causative agent of infectious mononucleosis and several malignancies involving lymphocytes and epithelial cells. We recently reported genomic analyses of chronic active EBV infection (CAEBV), a proliferative disorder of T and/or NK cells, as well as other lymphoid malignancies. We found that T and/or NK cells undergoing clonal expansion in CAEBV patients gain somatic driver mutations as the disorder progresses. Investigation of the viral genome revealed viral genomes harboring intragenic deletions in the BamHI-rightward transcripts (BART) region and in essential lytic genes. Interestingly, we observed that these deletions resulted in leaky expression of viral lytic genes. This increased expression of viral lytic genes is reminiscent of the "pre-latent abortive lytic" state, in which a substantial number of lytic genes are produced for weeks in the absence of progeny production, which contributes to cell survival upon de novo infection. It has been known that EBV can choose either latent or lytic state, but this dualistic concept may need to be reconsidered, as our data suggest the presence of the third, intermediate state; leaky expression of lytic genes that does not lead to completion of the full lytic amplification cycle. Leaky expression of lytic genes likely contributes to the formation and maintenance of several types of EBV-associated tumors. We also presented significant circumstantial evidence suggesting that EBV infects lymphoid progenitor cells in CAEBV before differentiation into T and NK cells. Taken together, our new data shed light on oncogenesis of CAEBV and other EBV-associated malignancies.
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Affiliation(s)
- Takayuki Murata
- Department of Virology and Parasitology, Fujita Health University School of Medicine, Toyoake, Japan.,Department of Virology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yusuke Okuno
- Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan
| | - Yoshitaka Sato
- Department of Virology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takahiro Watanabe
- Department of Virology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroshi Kimura
- Department of Virology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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50
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Montes-Mojarro IA, Kim WY, Fend F, Quintanilla-Martinez L. Epstein - Barr virus positive T and NK-cell lymphoproliferations: Morphological features and differential diagnosis. Semin Diagn Pathol 2019; 37:32-46. [PMID: 31889602 DOI: 10.1053/j.semdp.2019.12.004] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The spectrum of Epstein-Barr virus (EBV)-positive T and NK-cell lymphoproliferations is broad and ranges from reactive self-limited disorders to neoplastic processes with a fulminant clinical course. EBV plays an important role promoting lymphomagenesis, although the precise mechanisms remain elusive. EBV-positive lymphoproliferative disorders (LPD) are more common in East Asia (China, Japan, Korea and Taiwan), and Latin America suggesting a strong genetic predisposition. The revised 2016 World Health Organization (WHO) lymphoma classification recognizes the following malignant NK- and T-cell lymphomas; extranodal NK/T-cell lymphoma, nasal type (ENKTCL), aggressive NK-cell leukemia (ANKL), and the provisional entity within the group of peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) "primary EBV-positive nodal T or NK cell lymphoma". Disorders presenting mainly in children and young adults include chronic active EBV infection (CAEBV) - systemic and cutaneous forms - which are not considered malignant disorders but were included in the WHO classification for the first time because of the differential diagnosis with other T- or NK-cell lymphomas. CAEBV, cutaneous form, includes hydroa vacciniforme-like LPD (HV-LPD) and severe mosquito bite allergy (SMBA). Finally, systemic EBV-positive T-cell lymphoma of childhood was recognized as lymphoma because of its fulminant clinical course. Given the shared pathogenesis of these disorders, overlapping features are common demanding a close clinical, morphological and molecular correlation for an accurate diagnosis. This review summarizes the clinical, histopathological and molecular features of EBV-associated T and NK-cell LPD, highlighting the main features that might aid in the differential diagnosis.
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Affiliation(s)
- Ivonne A Montes-Mojarro
- Institute of Pathology and Neuropathology and Comprehensive Cancer Center Tübingen, University Hospital Tübingen, Eberhard-Karls-University, Tübingen, Germany
| | - Wook Youn Kim
- Institute of Pathology and Neuropathology and Comprehensive Cancer Center Tübingen, University Hospital Tübingen, Eberhard-Karls-University, Tübingen, Germany; Department of Pathology, Konkuk University School of Medicine, Seoul, Republic of Korea
| | - Falko Fend
- Institute of Pathology and Neuropathology and Comprehensive Cancer Center Tübingen, University Hospital Tübingen, Eberhard-Karls-University, Tübingen, Germany
| | - Leticia Quintanilla-Martinez
- Institute of Pathology and Neuropathology and Comprehensive Cancer Center Tübingen, University Hospital Tübingen, Eberhard-Karls-University, Tübingen, Germany.
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