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Jeong Y, Jang H, Kim SB, Yu M, Kim RE, Choi WS, Jeon Y, Lim JY. Dual targeting of EZH2 and PD-L1 in Burkitt's lymphoma enhances immune activation and induces apoptotic pathway. Front Immunol 2025; 16:1578665. [PMID: 40308579 PMCID: PMC12040923 DOI: 10.3389/fimmu.2025.1578665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Accepted: 04/01/2025] [Indexed: 05/02/2025] Open
Abstract
Introduction Enhancer of zeste homolog 2 (EZH2) catalyzes H3K27me3, an epigenetic modification linked to gene silencing, and its overexpression contributes to the progression of hematological malignancies. This study compares the efficacy of a conventional EZH2 inhibitor with a PROTAC-based EZH2 degrader in human lymphoma cell lines. Furthermore, we investigate the anti-tumor effects of combining EZH2 degrader with anti-PD-1, an immune checkpoint inhibitor, focusing on immune cell interactions and underlying mechanisms. Methods The cytotoxic effects of the EZH2 degrader and EZH2 inhibitor were evaluated in Burkitt's, B-cell, cutaneous T-cell, and Hodgkin's lymphoma cell lines. Additionally, the combination therapy of the EZH2 degrader and anti-PD-1 was assessed both in vitro and in a hu-PBMC-CDX mouse model. Results We evaluated the effects of an EZH2 degrader on seven lymphoma cell lines and observed significant reductions in cell viability compared to EZH2 inhibitor, particularly in Burkitt's lymphoma cell lines. EZH2 degrader treatment reduced EZH2 and c-Myc expression, induced G2/M cell cycle arrest, and increased apoptosis markers, including cleaved caspase-3 and cleaved PARP. Furthermore, Burkitt's lymphoma is a PD-L1 negative tumor; however, treatment with the EZH2 degrader resulted in a slight increase in PD-L1 expression. Combining EZH2 degrader with anti-PD-1 significantly enhanced anti-tumor effects compared to monotherapy. In vivo studies using a humanized lymphoma mouse model demonstrated a synergistic anti-tumor effect of EZH2 degrader and anti-PD-1, which was attributed to apoptosis-related pathways. Discussion These findings aim to provide insights into the therapeutic potential of targeting EZH2 in combination with immune checkpoint inhibitors for improved treatment of lymphomas.
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Affiliation(s)
- Yurim Jeong
- Department of Biomedical Laboratory Science, Inje University, Gimhae, Republic of Korea
| | - Hyewon Jang
- Department of Biomedical Laboratory Science, Inje University, Gimhae, Republic of Korea
| | - Se Been Kim
- Department of Biomedical Laboratory Science, Inje University, Gimhae, Republic of Korea
| | - Minseo Yu
- Department of Biomedical Laboratory Science, Inje University, Gimhae, Republic of Korea
| | - Ra Eun Kim
- Department of Biomedical Laboratory Science, Inje University, Gimhae, Republic of Korea
| | - Wan-Su Choi
- Department of Biomedical Laboratory Science, Inje University, Gimhae, Republic of Korea
| | - Youngwoo Jeon
- Department of Hematology, Yeouido St. Mary Hospital, School of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jung-Yeon Lim
- Department of Biomedical Laboratory Science, Inje University, Gimhae, Republic of Korea
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Koduru P, Chen W, Fuda F, Pacheco M, Garcia R. MYC-r with a non-IG partner concurrently with a cryptic t(12;21) in B-lymphoblastic leukemia: A case and prognostic significance. Cancer Genet 2025; 292-293:85-91. [PMID: 39983666 DOI: 10.1016/j.cancergen.2025.01.008] [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: 12/23/2024] [Revised: 01/30/2025] [Accepted: 01/30/2025] [Indexed: 02/23/2025]
Abstract
B-lymphoblastic leukemia (B-ALL) in children is characterized by recurrent chromosomal rearrangements that mostly have prognostic value. MYC rearrangements (MYC-r), typically associated with Burkitt lymphoma or mature B-cell neoplasms are infrequent in B-ALL. We report here a unique case of childhood B-ALL with concurrent MYC-r with a non-IG partner and a cryptic t(12;21). Leukemic cells had lymphoblastic morphology. Immunophenotypically, leukemic blasts were CD10 (+, slightly bright), CD15 (few +), CD19 (+), CD20 (+, partial), CD22 (+), CD34 (-), CD38 (+, slightly variably), CD45 (+, partial), cytoplasmic CD79a (+), HLA-DR (+), surface Ig (-), MPO (-), and TdT (+, partially). This immunophenotype was consistent with B-ALL. Cytogenetically, the karyotype was complex including a t(4;8)(q31;q24), and FISH analysis showed MYC-r, ETV6::RUNX1 and loss of ETV6 allele. The patient has been in complete remission for 11 years following the diagnosis. We reviewed cases of B-ALL with double leukemogenic alterations and MYC-r with non-IG partners to understand the clinical outcome in these rare patients.
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Affiliation(s)
- Prasad Koduru
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA.
| | - Weina Chen
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Franklin Fuda
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Martha Pacheco
- Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX, USA; Current address: St. Lukes Children's Cancer Institute, Boise, ID, USA
| | - Rolando Garcia
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA
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3
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Gagnon MF, Bruehl FK, Sill DR, Meyer RG, Greipp PT, Hoppman NL, Xu X, Baughn LB, Peterson JF, McPhail ED, Ketterling RP, King RL. Cytogenetic and pathologic characterization of MYC-rearranged B-cell lymphomas in pediatric and young adult patients. J Hematop 2024; 17:51-61. [PMID: 38561469 PMCID: PMC11127862 DOI: 10.1007/s12308-024-00579-6] [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: 02/12/2024] [Accepted: 03/19/2024] [Indexed: 04/04/2024] Open
Abstract
MYC-rearranged B-cell lymphoma (BCL) in the pediatric/young adult (YA) age group differs substantially in disease composition from adult cohorts. However, data regarding the partner genes, concurrent rearrangements, and ultimate diagnoses in these patients is scarce compared to that in adult cohorts. We aimed to characterize the spectrum of MYC-rearranged (MYC-R) mature, aggressive BCL in the pediatric/YA population. A retrospective study of morphologic, immunophenotypic, and fluorescence in situ hybridization (FISH) results of patients age ≤ 30 years with suspected Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBCL), and a MYC-R by FISH between 2013-2022 was performed. Two-hundred fifty-eight cases (129 (50%) pediatric (< 18 years) and 129 (50%) YA (18-30 years)) were included. Most MYC-R BCL in pediatric (89%) and YA (66%) cases were BL. While double-hit (DH) cytogenetics (MYC with BCL2 and/or BCL6-R, HGBCL-DH) was rare in the pediatric population (2/129, 2%), HGBCL-DH increased with age and was identified in 17/129 (13%) of YA cases. Most HGBCL-DH had MYC and BCL6-R, while BCL2-R were rare in both groups (3/258, 1%). MYC-R without an IG partner was more common in the YA group (14/116 (12%) vs 2/128 (2%), p = 0.001). The pediatric to YA transition is characterized by decreasing frequency in BL and increasing genetic heterogeneity of MYC-R BCL, with emergence of DH-BCL with MYC and BCL6-R. FISH to evaluate for BCL2 and BCL6 rearrangements is likely not warranted in the pediatric population but should continue to be applied in YA BCL.
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Affiliation(s)
- Marie-France Gagnon
- Division of Laboratory Genetics and Genomics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Frido K Bruehl
- Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Daniel R Sill
- Division of Laboratory Genetics and Genomics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Reid G Meyer
- Division of Laboratory Genetics and Genomics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Patricia T Greipp
- Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Nicole L Hoppman
- Division of Laboratory Genetics and Genomics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Xinjie Xu
- Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Linda B Baughn
- Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Jess F Peterson
- Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Ellen D McPhail
- Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Rhett P Ketterling
- Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Rebecca L King
- Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
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Xu YF, Wang GY, Zhang MY, Yang JG. Hub genes and their key effects on prognosis of Burkitt lymphoma. World J Clin Oncol 2023; 14:357-372. [PMID: 37970111 PMCID: PMC10631346 DOI: 10.5306/wjco.v14.i10.357] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 09/06/2023] [Accepted: 09/18/2023] [Indexed: 10/24/2023] Open
Abstract
BACKGROUND Burkitt lymphoma (BL) is an exceptionally aggressive malignant neoplasm that arises from either the germinal center or post-germinal center B cells. Patients with BL often present with rapid tumor growth and require high-intensity multi-drug therapy combined with adequate intrathecal chemotherapy prophylaxis, however, a standard treatment program for BL has not yet been established. It is important to identify biomarkers for predicting the prognosis of BLs and discriminating patients who might benefit from the therapy. Microarray data and sequencing information from public databases could offer opportunities for the discovery of new diagnostic or therapeutic targets. AIM To identify hub genes and perform gene ontology (GO) and survival analysis in BL. METHODS Gene expression profiles and clinical traits of BL patients were collected from the Gene Expression Omnibus database. Weighted gene co-expression network analysis (WGCNA) was applied to construct gene co-expression modules, and the cytoHubba tool was used to find the hub genes. Then, the hub genes were analyzed using GO and Kyoto Encyclopedia of Genes and Genomes analysis. Additionally, a Protein-Protein Interaction network and a Genetic Interaction network were constructed. Prognostic candidate genes were identified through overall survival analysis. Finally, a nomogram was established to assess the predictive value of hub genes, and drug-gene interactions were also constructed. RESULTS In this study, we obtained 8 modules through WGCNA analysis, and there was a significant correlation between the yellow module and age. Then we identified 10 hub genes (SRC, TLR4, CD40, STAT3, SELL, CXCL10, IL2RA, IL10RA, CCR7 and FCGR2B) by cytoHubba tool. Within these hubs, two genes were found to be associated with OS (CXCL10, P = 0.029 and IL2RA, P = 0.0066) by survival analysis. Additionally, we combined these two hub genes and age to build a nomogram. Moreover, the drugs related to IL2RA and CXCL10 might have a potential therapeutic role in relapsed and refractory BL. CONCLUSION From WGCNA and survival analysis, we identified CXCL10 and IL2RA that might be prognostic markers for BL.
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Affiliation(s)
- Yan-Feng Xu
- Department of Nuclear Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Guan-Yun Wang
- Department of Nuclear Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Ming-Yu Zhang
- Department of Nuclear Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Ji-Gang Yang
- Department of Nuclear Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
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Oliveira FMD, Souza VGD, Carvalho ADL, Lizarte Neto FS, Miranda CSS. Amplifications of AURKA and AURKB in a Burkitt lymphoma immunodeficiency-associated type: a case report. EINSTEIN-SAO PAULO 2023; 21:eRC0378. [PMID: 37436268 DOI: 10.31744/einstein_journal/2023rc0378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 03/19/2023] [Indexed: 07/13/2023] Open
Abstract
In equatorial Brazil, the association of Burkitt lymphoma and Epstein-Barr virus manifests at high rates. Here, we report, for the first time, amplifications of aurora kinase genes (AURKA/B) in a patient with a history of periodontal abscess and the presence of a remaining nodule, diagnosed with Burkitt lymphoma and Epstein-Barr virus, and /HIV positive. The patient was a 38-year-old man who presented with a 2-week-old severe jaw pain and a 3-day-old severe bilateral headache. He had a history of human papilloma virus. Interphase FISH analysis showed AURKA and AURKB amplification. The patient's condition worsened, progressing to death a month after the initial care. Changes in the MYCC and AURKA pathways are directly associated with genomic instability. Thus, MYCC rearrangements and higher expression of AURKA/B may be associated with therapy resistance, highlighting the importance of AURKA/B evaluation in Burkitt lymphoma.
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Al-Khreisat MJ, Ismail NH, Tabnjh A, Hussain FA, Mohamed Yusoff AA, Johan MF, Islam MA. Worldwide Prevalence of Epstein-Barr Virus in Patients with Burkitt Lymphoma: A Systematic Review and Meta-Analysis. Diagnostics (Basel) 2023; 13:2068. [PMID: 37370963 DOI: 10.3390/diagnostics13122068] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 05/28/2023] [Accepted: 06/07/2023] [Indexed: 06/29/2023] Open
Abstract
Burkitt lymphoma (BL) is a form of B-cell malignancy that progresses aggressively and is most often seen in children. While Epstein-Barr virus (EBV) is a double-stranded DNA virus that has been linked to a variety of cancers, it can transform B lymphocytes into immortalized cells, as shown in BL. Therefore, the estimated prevalence of EBV in a population may assist in the prediction of whether this population has a high risk of increased BL cases. This systematic review and meta-analysis aimed to estimate the prevalence of Epstein-Barr virus in patients with Burkitt lymphoma. Using the appropriate keywords, four electronic databases were searched. The quality of the included studies was assessed using the Joanna Briggs Institute's critical appraisal tool. The results were reported as percentages with a 95% confidence interval using a random-effects model (CI). PROSPERO was used to register the protocol (CRD42022372293), and 135 studies were included. The prevalence of Epstein-Barr virus in patients with Burkitt lymphoma was 57.5% (95% CI: 51.5 to 63.4, n = 4837). The sensitivity analyses demonstrated consistent results, and 65.2% of studies were of high quality. Egger's test revealed that there was a significant publication bias. EBV was found in a significantly high proportion of BL patients (more than 50% of BL patients). This study recommends EBV testing as an alternative for predictions and the assessment of the clinical disease status of BL.
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Affiliation(s)
- Mutaz Jamal Al-Khreisat
- Department of Haematology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia
| | - Nor Hayati Ismail
- Department of Haematology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia
| | - Abedelmalek Tabnjh
- Department of Applied Dental Sciences, Faculty of Applied Medical Sciences, Jordan University of Science and Technology, Irbid 22110, Jordan
| | - Faezahtul Arbaeyah Hussain
- Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia
| | - Abdul Aziz Mohamed Yusoff
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia
| | - Muhammad Farid Johan
- Department of Haematology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia
| | - Md Asiful Islam
- WHO Collaborating Centre for Global Women's Health, Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
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Kovach AE, Raca G. Modern Classification and Management of Pediatric B-cell Leukemia and Lymphoma. Surg Pathol Clin 2023; 16:249-266. [PMID: 37149359 DOI: 10.1016/j.path.2023.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/11/2023]
Abstract
Although pediatric hematopathology overlaps with that of adults, certain forms of leukemia and lymphoma, and many types of reactive conditions affecting the bone marrow and lymph nodes, are unique to children. As part of this series focused on lymphomas, this article (1) details the novel subtypes of lymphoblastic leukemia seen primarily in children and described since the 2017 World Health Organization classification and (2) discusses unique concepts in pediatric hematopathology, including nomenclature changes and evaluation of surgical margins in selected lymphomas.
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Affiliation(s)
- Alexandra E Kovach
- Division of Laboratory Medicine, Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA, USA; Clinical Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA.
| | - Gordana Raca
- Clinical Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA; Division of Genomic Medicine, Department of Pathology and Laboratory Medicine, Center for Personalized Medicine, Children's Hospital Los Angeles, Los Angeles, CA, USA
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8
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Ribeiro ML, Profitós-Pelejà N, Santos JC, Blecua P, Reyes-Garau D, Armengol M, Fernández-Serrano M, Miskin HP, Bosch F, Esteller M, Normant E, Roué G. G protein-coupled receptor 183 mediates the sensitization of Burkitt lymphoma tumors to CD47 immune checkpoint blockade by anti-CD20/PI3Kδi dual therapy. Front Immunol 2023; 14:1130052. [PMID: 37153563 PMCID: PMC10160608 DOI: 10.3389/fimmu.2023.1130052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 04/10/2023] [Indexed: 05/09/2023] Open
Abstract
Background Immunotherapy-based regimens have considerably improved the survival rate of B-cell non-Hodgkin lymphoma (B-NHL) patients in the last decades; however, most disease subtypes remain almost incurable. TG-1801, a bispecific antibody that targets CD47 selectively on CD19+ B-cells, is under clinical evaluation in relapsed/refractory (R/R) B-NHL patients either as a single-agent or in combination with ublituximab, a new generation CD20 antibody. Methods A set of eight B-NHL cell lines and primary samples were cultured in vitro in the presence of bone marrow-derived stromal cells, M2-polarized primary macrophages, and primary circulating PBMCs as a source of effector cells. Cell response to TG-1801 alone or combined with the U2 regimen associating ublituximab to the PI3Kδ inhibitor umbralisib, was analyzed by proliferation assay, western blot, transcriptomic analysis (qPCR array and RNA sequencing followed by gene set enrichment analysis) and/or quantification of antibody-dependent cell death (ADCC) and antibody-dependent cell phagocytosis (ADCP). CRISPR-Cas9 gene edition was used to selectively abrogate GPR183 gene expression in B-NHL cells. In vivo, drug efficacy was determined in immunodeficient (NSG mice) or immune-competent (chicken embryo chorioallantoic membrane (CAM)) B-NHL xenograft models. Results Using a panel of B-NHL co-cultures, we show that TG-1801, by disrupting the CD47-SIRPα axis, potentiates anti-CD20-mediated ADCC and ADCP. This led to a remarkable and durable antitumor effect of the triplet therapy composed by TG-1801 and U2 regimen, in vitro, as well as in mice and CAM xenograft models of B-NHL. Transcriptomic analysis also uncovered the upregulation of the G protein-coupled and inflammatory receptor, GPR183, as a crucial event associated with the efficacy of the triplet combination. Genetic depletion and pharmacological inhibition of GPR183 impaired ADCP initiation, cytoskeleton remodeling and cell migration in 2D and 3D spheroid B-NHL co-cultures, and disrupted macrophage-mediated control of tumor growth in B-NHL CAM xenografts. Conclusions Altogether, our results support a crucial role for GPR183 in the recognition and elimination of malignant B cells upon concomitant targeting of CD20, CD47 and PI3Kδ, and warrant further clinical evaluation of this triplet regimen in B-NHL.
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Affiliation(s)
- Marcelo Lima Ribeiro
- Lymphoma Translational Group, Josep Carreras Leukemia Research Institute, Badalona, Spain
- Laboratory of Immunopharmacology and Molecular Biology, Sao Francisco University Medical School, Braganca Paulista, São Paulo, Brazil
| | - Núria Profitós-Pelejà
- Lymphoma Translational Group, Josep Carreras Leukemia Research Institute, Badalona, Spain
| | | | - Pedro Blecua
- Cancer Epigenetics Group, Josep Carreras Leukemia Research Institute, Badalona, Spain
| | - Diana Reyes-Garau
- Lymphoma Translational Group, Josep Carreras Leukemia Research Institute, Badalona, Spain
| | - Marc Armengol
- Lymphoma Translational Group, Josep Carreras Leukemia Research Institute, Badalona, Spain
- Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona, Barcelona, Spain
| | - Miranda Fernández-Serrano
- Lymphoma Translational Group, Josep Carreras Leukemia Research Institute, Badalona, Spain
- Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona, Barcelona, Spain
| | | | - Francesc Bosch
- Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona, Barcelona, Spain
- Department of Hematology, Vall d’Hebron University Hospital, Barcelona, Spain
- Experimental Hematology, Vall d’Hebron Institute of Oncology, Barcelona, Spain
| | - Manel Esteller
- Cancer Epigenetics Group, Josep Carreras Leukemia Research Institute, Badalona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, Barcelona, Spain
- Instituciò Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
| | | | - Gael Roué
- Lymphoma Translational Group, Josep Carreras Leukemia Research Institute, Badalona, Spain
- Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona, Barcelona, Spain
- Department of Hematology, Vall d’Hebron University Hospital, Barcelona, Spain
- Experimental Hematology, Vall d’Hebron Institute of Oncology, Barcelona, Spain
- *Correspondence: Gael Roué,
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López C, Burkhardt B, Chan JKC, Leoncini L, Mbulaiteye SM, Ogwang MD, Orem J, Rochford R, Roschewski M, Siebert R. Burkitt lymphoma. Nat Rev Dis Primers 2022; 8:78. [PMID: 36522349 DOI: 10.1038/s41572-022-00404-3] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/19/2022] [Indexed: 12/16/2022]
Abstract
Burkitt lymphoma (BL) is an aggressive form of B cell lymphoma that can affect children and adults. The study of BL led to the identification of the first recurrent chromosomal aberration in lymphoma, t(8;14)(q24;q32), and subsequent discovery of the central role of MYC and Epstein-Barr virus (EBV) in tumorigenesis. Most patients with BL are cured with chemotherapy but those with relapsed or refractory disease usually die of lymphoma. Historically, endemic BL, non-endemic sporadic BL and the immunodeficiency-associated BL have been recognized, but differentiation of these epidemiological variants is confounded by the frequency of EBV positivity. Subtyping into EBV+ and EBV- BL might better describe the biological heterogeneity of the disease. Phenotypically resembling germinal centre B cells, all types of BL are characterized by dysregulation of MYC due to enhancer activation via juxtaposition with one of the three immunoglobulin loci. Additional molecular changes commonly affect B cell receptor and sphingosine-1-phosphate signalling, proliferation, survival and SWI-SNF chromatin remodelling. BL is diagnosed on the basis of morphology and high expression of MYC. BL can be effectively treated in children and adolescents with short durations of high dose-intensity multiagent chemotherapy regimens. Adults are more susceptible to toxic effects but are effectively treated with chemotherapy, including modified versions of paediatric regimens. The outcomes in patients with BL are good in high-income countries with low mortality and few late effects, but in low-income and middle-income countries, BL is diagnosed late and is usually treated with less-effective regimens affecting the overall good outcomes in patients with this lymphoma.
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Affiliation(s)
- Cristina López
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany
| | - Birgit Burkhardt
- Non-Hodgkin's Lymphoma Berlin-Frankfurt-Münster (NHL-BFM) Study Center and Paediatric Hematology, Oncology and BMT, University Hospital Muenster, Muenster, Germany
| | - John K C Chan
- Department of Pathology, Queen Elizabeth Hospital, Hong Kong SAR, China
| | - Lorenzo Leoncini
- Section of Pathology, Department of Medical Biotechnology, University of Siena, Siena, Italy
| | - Sam M Mbulaiteye
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD, USA
| | | | | | - Rosemary Rochford
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Mark Roschewski
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Reiner Siebert
- Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany.
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10
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Brunner JR, Altshuler E, Yang LJ. Analysis of the Diagnosis of Burkitt-Like Lymphoma in a Patient With Atypical Cytogenetics and Molecular Markers. Cureus 2022; 14:e28295. [PMID: 36158446 PMCID: PMC9494575 DOI: 10.7759/cureus.28295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/22/2022] [Indexed: 11/29/2022] Open
Abstract
The World Health Organization (WHO) criteria for diagnosis of hematopoietic and lymphoid cancers serve as a useful tool for distinguishing between malignant conditions based on phenotypic, morphologic, and/or cytogenetic presentations, but their utility is limited in patients whose diseases contain elements of multiple diagnoses. We present a case of a 59-year-old male with enlargement of muscular and soft tissues of the left hip and an intraconal soft tissue mass surrounding the left optic nerve, who was treated for Burkitt-like lymphoma (BLL). Cytogenetics revealed the absence of an MYC rearrangement involving chromosomes 2, 14, or 22, normally found in Burkitt lymphoma, or the classic telomeric losses and proximal gains observed in BLL. Diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS) and high-grade B-cell lymphoma, not otherwise specified (HGBL, NOS) were also considered as possible diagnoses. The persistence of ambiguous lymphoma diagnoses demonstrates the need for both continued research in the area and regular revision of the WHO criteria. Physicians working with patients with poorly defined lymphomas should defer to diagnostic algorithms where applicable, many of which have been proposed in the literature.
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11
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Li MJ, Yu CH, Chou SW, Su YH, Liao KW, Chang HH, Yang YL. TCF3-HLF-Positive Acute Lymphoblastic Leukemia Resembling Burkitt Leukemia: Cell Morphologic and Immunophenotypic Findings. JCO Precis Oncol 2022; 6:e2200236. [PMID: 36001860 PMCID: PMC9489183 DOI: 10.1200/po.22.00236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2022] Open
Affiliation(s)
- Meng-Ju Li
- Department of Pediatrics, National Taiwan University Hsin-Chu Hospital, Hsinchu, Taiwan.,Department of Biological Science and Technology, College of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
| | - Chih-Hsiang Yu
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.,Department of Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Shu-Wei Chou
- Department of Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Ying-Hui Su
- Department of Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.,Childhood Cancer Foundation of the Republic of China, Taipei, Taiwan
| | - Kuang-Wen Liao
- Department of Biological Science and Technology, College of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan.,Institute of Molecular Medicine and Bioengineering, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
| | - Hsiu-Hao Chang
- Department of Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yung-Li Yang
- Department of Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Laboratory Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
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12
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Schubert J, Wu J, Li MM, Cao K. Best Practice for Clinical Somatic Variant Interpretation and Reporting. Clin Lab Med 2022; 42:423-434. [DOI: 10.1016/j.cll.2022.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
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13
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García R, Hussain A, Chen W, Wilson K, Koduru P. An artificial intelligence system applied to recurrent cytogenetic aberrations and genetic progression scores predicts MYC rearrangements in large B-cell lymphoma. EJHAEM 2022; 3:707-721. [PMID: 36051032 PMCID: PMC9421965 DOI: 10.1002/jha2.451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 04/05/2022] [Accepted: 04/09/2022] [Indexed: 11/20/2022]
Abstract
Diffuse large B-cell lymphoma (DLBCL), the most common type of non-Hodgkin lymphoma, is characterized by MYC rearrangements (MYC R) in up to 15% of cases, and these have unfavorable prognosis. Due to cryptic rearrangements and variations in MYC breakpoints, MYC R may be undetectable by conventional methods in up to 10%-15% of cases. In this study, a retrospective proof of concept study, we sought to identify recurrent cytogenetic aberrations (RCAs), generate genetic progression scores (GP) from RCAs and apply these to an artificial intelligence (AI) algorithm to predict MYC status in the karyotypes of published cases. The developed AI algorithm is validated for its performance on our institutional cases. In addition, cytogenetic evolution pattern and clinical impact of RCAs was performed. Chromosome losses were associated with MYC-, while partial gain of chromosome 1 was significant in MYC R tumors. MYC R was the sole driver alteration in MYC-rearranged tumors, and evolution patterns revealed RCAs associated with gene expression signatures. A higher GPS value was associated with MYC R tumors. A subsequent AI algorithm (composed of RCAs + GPS) obtained a sensitivity of 91.4 and specificity of 93.8 at predicting MYC R. Analysis of an additional 59 institutional cases with the AI algorithm showed a sensitivity and specificity of 100% and 87% each with positive predictive value of 92%, and a negative predictive value of 100%. Cases with a MYC R showed a shorter survival.
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Affiliation(s)
- Rolando García
- Department of PathologyUT Southwestern Medical CenterDallasTexasUSA
| | - Anas Hussain
- Deccan College of Medical SciencesHyderabadIndia
| | - Weina Chen
- Department of PathologyUT Southwestern Medical CenterDallasTexasUSA
| | - Kathleen Wilson
- Department of PathologyUT Southwestern Medical CenterDallasTexasUSA
| | - Prasad Koduru
- Department of PathologyUT Southwestern Medical CenterDallasTexasUSA
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14
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Burkhardt B, Michgehl U, Rohde J, Erdmann T, Berning P, Reutter K, Rohde M, Borkhardt A, Burmeister T, Dave S, Tzankov A, Dugas M, Sandmann S, Fend F, Finger J, Mueller S, Gökbuget N, Haferlach T, Kern W, Hartmann W, Klapper W, Oschlies I, Richter J, Kontny U, Lutz M, Maecker-Kolhoff B, Ott G, Rosenwald A, Siebert R, von Stackelberg A, Strahm B, Woessmann W, Zimmermann M, Zapukhlyak M, Grau M, Lenz G. Clinical relevance of molecular characteristics in Burkitt lymphoma differs according to age. Nat Commun 2022; 13:3881. [PMID: 35794096 PMCID: PMC9259584 DOI: 10.1038/s41467-022-31355-8] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 06/13/2022] [Indexed: 11/09/2022] Open
Abstract
While survival has improved for Burkitt lymphoma patients, potential differences in outcome between pediatric and adult patients remain unclear. In both age groups, survival remains poor at relapse. Therefore, we conducted a comparative study in a large pediatric cohort, including 191 cases and 97 samples from adults. While TP53 and CCND3 mutation frequencies are not age related, samples from pediatric patients showed a higher frequency of mutations in ID3, DDX3X, ARID1A and SMARCA4, while several genes such as BCL2 and YY1AP1 are almost exclusively mutated in adult patients. An unbiased analysis reveals a transition of the mutational profile between 25 and 40 years of age. Survival analysis in the pediatric cohort confirms that TP53 mutations are significantly associated with higher incidence of relapse (25 ± 4% versus 6 ± 2%, p-value 0.0002). This identifies a promising molecular marker for relapse incidence in pediatric BL which will be used in future clinical trials.
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Affiliation(s)
- Birgit Burkhardt
- Pediatric Hematology, Oncology and BMT, University Hospital Münster, Münster, Germany.
| | - Ulf Michgehl
- Pediatric Hematology, Oncology and BMT, University Hospital Münster, Münster, Germany
| | - Jonas Rohde
- Pediatric Hematology, Oncology and BMT, University Hospital Münster, Münster, Germany
| | - Tabea Erdmann
- Department of Medicine A, Hematology, Oncology, and Pneumology, University Hospital Münster, Münster, Germany
| | - Philipp Berning
- Department of Medicine A, Hematology, Oncology, and Pneumology, University Hospital Münster, Münster, Germany
| | - Katrin Reutter
- Pediatric Hematology, Oncology and BMT, University Hospital Münster, Münster, Germany
| | - Marius Rohde
- Pediatric Hematology and Oncology, University Hospital Giessen, Giessen, Germany
| | - Arndt Borkhardt
- Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Thomas Burmeister
- Department of Hematology, Oncology and Tumor Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Sandeep Dave
- Center for Genomic and Computational Biology and Department of Medicine, Duke University, Durham, NC, USA
| | - Alexandar Tzankov
- Pathology, Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
| | - Martin Dugas
- Institute of Medical Informatics, Heidelberg University Hospital, Heidelberg, Germany
| | - Sarah Sandmann
- Institute of Medical Informatics, University of Münster, Münster, Germany
| | - Falko Fend
- Institute of Pathology and Neuropathology and Comprehensive Cancer Centre Tübingen, University Hospital Tübingen, Eberhard-Karls-University, Tübingen, Germany
| | - Jasmin Finger
- Pediatric Hematology, Oncology and BMT, University Hospital Münster, Münster, Germany
| | - Stephanie Mueller
- Pediatric Hematology, Oncology and BMT, University Hospital Münster, Münster, Germany
| | - Nicola Gökbuget
- Department of Medicine II, Goethe University, Frankfurt, Germany
| | | | | | - Wolfgang Hartmann
- Division of Translational Pathology, Gerhard-Domagk-Institute of Pathology, University Hospital of Münster, Münster, Germany
| | - Wolfram Klapper
- Department of Pathology, Hematopathology Section, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Ilske Oschlies
- Department of Pathology, Hematopathology Section, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Julia Richter
- Department of Pathology, Hematopathology Section, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Udo Kontny
- Section of Pediatric Hematology, Oncology, and Stem Cell Transplantation, Department of Pediatric and Adolescent Medicine, RWTH Aachen University Hospital, Aachen, Germany
| | - Mathias Lutz
- Hematology and Oncology, Medical Faculty, University of Augsburg, Augsburg, Germany
| | - Britta Maecker-Kolhoff
- Hannover Medical School, Department of Pediatric Hematology and Oncology, Hannover, Germany
| | - German Ott
- Department of Clinical Pathology, Robert-Bosch-Krankenhaus, and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
| | - Andreas Rosenwald
- Institute of Pathology, Universität Würzburg and Comprehensive Cancer Centre Mainfranken (CCCMF), Würzburg, Germany
| | - Reiner Siebert
- Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany
| | - Arend von Stackelberg
- Department of Pediatric Oncology Hematology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Brigitte Strahm
- Department of Pediatrics and Adolescent Medicine Division of Pediatric Hematology and Oncology, Medical Center Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany
| | - Wilhelm Woessmann
- Pediatric Hematology and Oncology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Martin Zimmermann
- Hannover Medical School, Department of Pediatric Hematology and Oncology, Hannover, Germany
| | - Myroslav Zapukhlyak
- Department of Medicine A, Hematology, Oncology, and Pneumology, University Hospital Münster, Münster, Germany
| | - Michael Grau
- Department of Medicine A, Hematology, Oncology, and Pneumology, University Hospital Münster, Münster, Germany
| | - Georg Lenz
- Department of Medicine A, Hematology, Oncology, and Pneumology, University Hospital Münster, Münster, Germany
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15
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Möker P, zur Stadt U, Zimmermann M, Alawi M, Mueller S, Finger J, Knörr F, Riquelme A, Oschlies I, Klapper W, Bradtke J, Burkhardt B, Woessmann W, Damm-Welk C. Characterization of IG-MYC-breakpoints and their application for quantitative minimal disease monitoring in high-risk pediatric Burkitt-lymphoma and -leukemia. Leukemia 2022; 36:2343-2346. [PMID: 35790817 PMCID: PMC9417994 DOI: 10.1038/s41375-022-01626-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 06/02/2022] [Accepted: 06/07/2022] [Indexed: 12/02/2022]
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16
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Sang W, Tu D, Zhang M, Qin Y, Yin W, Song X, Sun C, Yan D, Wang X, Zeng L, Li Z, Xu K, Xu L. l-Asparaginase synergizes with etoposide via the PI3K/Akt/mTOR pathway in Epstein-Barr virus-positive Burkitt lymphoma. J Biochem Mol Toxicol 2022; 36:e23117. [PMID: 35757978 DOI: 10.1002/jbt.23117] [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: 09/24/2021] [Revised: 04/24/2022] [Accepted: 05/18/2022] [Indexed: 11/09/2022]
Abstract
Burkitt lymphoma (BL) is an aggressive Epstein-Barr virus (EBV)-driven B-cell lymphoma characterized by the translocation and rearrangement of the c-Myc proto-oncogene. High-intensity multidrug chemotherapy regimens have a limited effect on the survival of refractory or relapsed BL patients, mainly owing to the high EBV load and drug resistance. l-asparaginase ( l-Asp) and etoposide (VP-16) play a beneficial role in EBV-related lymphoproliferative diseases; however, their roles and mechanisms in BL remain unclear. In this study, we found that VP-16 inhibited BL cell proliferation and arrested the cell cycle at the G2 /M phase. It also induced autophagy and activated the extrinsic and intrinsic apoptotic signaling pathways in BL cells. Mechanistically, VP-16 inhibited c-Myc expression and regulated the PI3K/Akt/mTOR signaling pathway. Notably, VP-16 also showed a specific synergistic effect with l-Asp to induce apoptosis in EBV-positive BL cells but not in EBV-negative BL cells. VP-16 combined with l-Asp further inhibited c-Myc expression and downregulated the PI3K/Akt/mTOR signaling pathway. Additionally, we found that VP-16 inhibited the expression of latent membrane protein 1 (LMP1), and in combination with l-Asp further decreased LMP1 expression in Raji cells. Our in vivo data also showed that the dual-drug combination significantly inhibited the growth of BL tumors and prolonged the survival of mice compared to VP-16 alone. In conclusion, this study provides new evidence that l-Asp may enhance the antitumor effect of VP-16 by inhibiting the PI3K/Akt/mTOR signaling pathway in EBV-positive BL cells.
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Affiliation(s)
- Wei Sang
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China.,Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.,Key Laboratory of Bone Marrow Stem Cell, Xuzhou, Jiangsu, China
| | - Dongyun Tu
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China.,Key Laboratory of Bone Marrow Stem Cell, Xuzhou, Jiangsu, China.,Department of Cardiology, Yancheng TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Yancheng, Jiangsu, China
| | - Meng Zhang
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China.,Key Laboratory of Bone Marrow Stem Cell, Xuzhou, Jiangsu, China
| | - Yuanyuan Qin
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China.,Key Laboratory of Bone Marrow Stem Cell, Xuzhou, Jiangsu, China
| | - Wenjing Yin
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China.,Key Laboratory of Bone Marrow Stem Cell, Xuzhou, Jiangsu, China
| | - Xuguang Song
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Cai Sun
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Dongmei Yan
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Xiangmin Wang
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Lingyu Zeng
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China.,Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.,Key Laboratory of Bone Marrow Stem Cell, Xuzhou, Jiangsu, China
| | - Zhenyu Li
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China.,Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.,Key Laboratory of Bone Marrow Stem Cell, Xuzhou, Jiangsu, China
| | - Kailin Xu
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China.,Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.,Key Laboratory of Bone Marrow Stem Cell, Xuzhou, Jiangsu, China
| | - Linyan Xu
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China.,Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.,Key Laboratory of Bone Marrow Stem Cell, Xuzhou, Jiangsu, China
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17
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Sheikh IN, Elgehiny A, Ragoonanan D, Mahadeo KM, Nieto Y, Khazal S. Management of Aggressive Non-Hodgkin Lymphomas in the Pediatric, Adolescent, and Young Adult Population: An Adult vs. Pediatric Perspective. Cancers (Basel) 2022; 14:2912. [PMID: 35740580 PMCID: PMC9221186 DOI: 10.3390/cancers14122912] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 06/04/2022] [Accepted: 06/08/2022] [Indexed: 02/01/2023] Open
Abstract
Non-Hodgkin lymphoma (NHL) is a broad entity which comprises a number of different types of lymphomatous malignancies. In the pediatric and adolescent population, the type and prognosis of NHL varies by age and gender. In comparison to adults, pediatric and adolescent patients generally have better outcomes following treatment for primary NHL. However, relapsed/refractory (R/R) disease is associated with poorer outcomes in many types of NHL such as diffuse large B cell lymphoma and Burkitt lymphoma. Newer therapies have been approved in the use of primary NHL in the pediatric and adolescent population such as Rituximab and other therapies such as chimeric antigen receptor T-cell (CAR T-cell) therapy are under investigation for the treatment of R/R NHL. In this review, we feature the characteristics, diagnosis, and treatments of the most common NHLs in the pediatric and adolescent population and also highlight the differences that exist between pediatric and adult disease. We then detail the areas of treatment advances such as immunotherapy with CAR T-cells, brentuximab vedotin, and blinatumomab as well as cell cycle inhibitors and describe areas where further research is needed. The aim of this review is to juxtapose established research regarding pediatric and adolescent NHL with recent advancements as well as highlight treatment gaps where more investigation is needed.
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Affiliation(s)
- Irtiza N. Sheikh
- Department of Pediatrics, Pediatric Hematology Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Amr Elgehiny
- Department of Pediatrics, McGovern Medical School, The University of Texas at Houston Health Science Center, Houston, TX 77030, USA;
| | - Dristhi Ragoonanan
- Department of Pediatrics, CARTOX Program, Pediatric Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (D.R.); (K.M.M.)
| | - Kris M. Mahadeo
- Department of Pediatrics, CARTOX Program, Pediatric Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (D.R.); (K.M.M.)
| | - Yago Nieto
- Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Sajad Khazal
- Department of Pediatrics, CARTOX Program, Pediatric Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (D.R.); (K.M.M.)
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18
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Calciolari B, Scarpinello G, Tubi LQ, Piazza F, Carrer A. Metabolic control of epigenetic rearrangements in B cell pathophysiology. Open Biol 2022; 12:220038. [PMID: 35580618 PMCID: PMC9113833 DOI: 10.1098/rsob.220038] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 04/26/2022] [Indexed: 01/04/2023] Open
Abstract
Both epigenetic and metabolic reprogramming guide lymphocyte differentiation and can be linked, in that metabolic inputs can be integrated into the epigenome to inform cell fate decisions. This framework has been thoroughly investigated in several pathophysiological contexts, including haematopoietic cell differentiation. In fact, metabolite availability dictates chromatin architecture and lymphocyte specification, a multi-step process where haematopoietic stem cells become terminally differentiated lymphocytes (effector or memory) to mount the adaptive immune response. B and T cell precursors reprogram their cellular metabolism across developmental stages, not only to meet ever-changing energetic demands but to impose chromatin accessibility and regulate the function of master transcription factors. Metabolic control of the epigenome has been extensively investigated in T lymphocytes, but how this impacts type-B life cycle remains poorly appreciated. This assay will review our current understanding of the connection between cell metabolism and epigenetics at crucial steps of B cell maturation and how its dysregulation contributes to malignant transformation.
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Affiliation(s)
- Beatrice Calciolari
- Department of Biology (DiBio), of the University of Padova, Padova, Italy
- Department of Medicine (DIMED), Hematology and Clinical Immunology Section, of the University of Padova, Padova, Italy
- Veneto Institute of Molecular Medicine (VIMM), Padova, Italy
| | - Greta Scarpinello
- Department of Surgical, Oncological and Gastroenterological Sciences (DiSCOG), of the University of Padova, Padova, Italy
| | - Laura Quotti Tubi
- Department of Medicine (DIMED), Hematology and Clinical Immunology Section, of the University of Padova, Padova, Italy
- Veneto Institute of Molecular Medicine (VIMM), Padova, Italy
| | - Francesco Piazza
- Department of Medicine (DIMED), Hematology and Clinical Immunology Section, of the University of Padova, Padova, Italy
- Veneto Institute of Molecular Medicine (VIMM), Padova, Italy
| | - Alessandro Carrer
- Department of Biology (DiBio), of the University of Padova, Padova, Italy
- Veneto Institute of Molecular Medicine (VIMM), Padova, Italy
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19
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Soyland DJ, Thanel PF, Sievers ME, Wagner K, Vuong SM. Primary epidural sporadic Burkitt lymphoma in a 3-year-old: Case report and literature review. Surg Neurol Int 2022; 13:106. [PMID: 35399880 PMCID: PMC8986637 DOI: 10.25259/sni_1172_2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 03/16/2022] [Indexed: 11/25/2022] Open
Abstract
Background: Burkitt lymphoma (BL) is a common tumor of childhood that usually arises in the abdomen or pelvis in its sporadic form. In a minority of cases, BL can present with CNS involvement, usually as a secondary site. Rarely, BL can arise primarily in the epidural space and present with back pain, or less commonly, acute myelopathy. This presentation is a surgical emergency and requires vigilant management. Case Description: We describe a case of pediatric BL arising primarily within the epidural space and presenting with progressive difficulty walking in a 3-year-old boy. Progression to complete inability to walk, absent lower extremity deep tendon reflexes, and new urinary incontinence prompted MRI of the spine, which showed a lesion extending from T5 to T10 and wrapping around the anterior and posterior portions of the spine with evidence of spinal cord compression. The patient underwent decompressive laminectomies from T5 to T10 and partial debulking of the posterior portions of the tumor. Microscopic examination showed a prominent “starry sky” pattern with abundant mitotic figures. Immunohistochemistry confirmed the diagnosis of BL. The patient is 10 months post-op and continues to undergo chemotherapy with partial neurologic improvement. He was free of recurrence 10 months post-operative. Conclusion: This appears to be the youngest described patient presenting with acute myelopathy in primary paraspinal BL. Management should include surgical decompression of the spinal cord followed by one of the various described chemotherapeutic regimens. Preoperative staging and neurologic function correlate with prognosis.
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Affiliation(s)
- Dallas J. Soyland
- Department of Neurosurgery, Sanford School of Medicine, Sioux Falls, South Dakota, United States
| | - Paul F. Thanel
- Department of Neurosurgery, Sanford School of Medicine, Sioux Falls, South Dakota, United States
| | - Meaghan E. Sievers
- Department of Neurosurgery, Sanford School of Medicine, Sioux Falls, South Dakota, United States
| | - Kayelyn Wagner
- Department of Pediatric Oncology, Sanford School of Medicine, Sioux Falls, South Dakota, United States
| | - Shawn M. Vuong
- Department of Neurosurgery, Sanford School of Medicine, Sioux Falls, South Dakota, United States
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20
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Tu DY, Zhang M, Yin WJ, Xu LY, Sang W, Li ZY, Xu KL. [Effects of L-asparaginase on proliferation, cell cycle and apoptosis of Burkitt lymphoma cell lines]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2021; 42:930-938. [PMID: 35045655 PMCID: PMC8763592 DOI: 10.3760/cma.j.issn.0253-2727.2021.11.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Indexed: 11/30/2022]
Abstract
Objective: To investigate the effect of L-asparaginase on the proliferation, cell cycle, and apoptosis of Burkitt lymphoma cell lines and explore the molecular mechanism. Methods: The effect of L-asparaginase on the cell proliferation of Burkitt lymphoma cell lines was detected using the CCK-8 method. The apoptosis rate and cell cycle were detected using flow cytometry. The expression of related molecules in cell cycle, apoptosis, autophagy, and PI3K/Akt/mTOR signaling pathway was detected and analyzed using qPCR and Western blot assay. Results: L-asparaginase significantly inhibited the proliferation of Burkitt lymphoma cell lines and caused cell cycle arrest at G(0)/G(1) phage. L-asparaginase induced cell apoptosis and autophagy in Burkitt lymphoma cell lines. Further results showed that L-asparaginase inhibited the expression of c-Myc and also inhibited the expression of p-PI3K, p-Akt-S473, p-mTOR, p-70S6K, and p-4E-BP1. Combining PI3K inhibitor LY294002 with L-asparaginase further induced apoptosis. Additionally, L-Asp inhibited STAT and ERK signaling pathways. Conclusion: L-asparaginase inhibited Burkitt lymphoma cell proliferation, arrested cell cycle, activated autophagy, and induced apoptosis by inhibiting the PI3K/Akt/mTOR signaling pathway.
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Affiliation(s)
- D Y Tu
- Institute of Hematology, Xuzhou Medical University, Cell Research and Transformation Center, Affiliated Hospital of Xuzhou Medical University, Department of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, China Department of Cardiology, Yancheng TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Yancheng 224000, China
| | - M Zhang
- Institute of Hematology, Xuzhou Medical University, Cell Research and Transformation Center, Affiliated Hospital of Xuzhou Medical University, Department of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, China
| | - W J Yin
- Institute of Hematology, Xuzhou Medical University, Cell Research and Transformation Center, Affiliated Hospital of Xuzhou Medical University, Department of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, China
| | - L Y Xu
- Institute of Hematology, Xuzhou Medical University, Cell Research and Transformation Center, Affiliated Hospital of Xuzhou Medical University, Department of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, China
| | - W Sang
- Institute of Hematology, Xuzhou Medical University, Cell Research and Transformation Center, Affiliated Hospital of Xuzhou Medical University, Department of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, China
| | - Z Y Li
- Institute of Hematology, Xuzhou Medical University, Cell Research and Transformation Center, Affiliated Hospital of Xuzhou Medical University, Department of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, China
| | - K L Xu
- Institute of Hematology, Xuzhou Medical University, Cell Research and Transformation Center, Affiliated Hospital of Xuzhou Medical University, Department of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, China
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21
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Ahmadi SE, Rahimi S, Zarandi B, Chegeni R, Safa M. MYC: a multipurpose oncogene with prognostic and therapeutic implications in blood malignancies. J Hematol Oncol 2021; 14:121. [PMID: 34372899 PMCID: PMC8351444 DOI: 10.1186/s13045-021-01111-4] [Citation(s) in RCA: 102] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 06/12/2021] [Indexed: 12/17/2022] Open
Abstract
MYC oncogene is a transcription factor with a wide array of functions affecting cellular activities such as cell cycle, apoptosis, DNA damage response, and hematopoiesis. Due to the multi-functionality of MYC, its expression is regulated at multiple levels. Deregulation of this oncogene can give rise to a variety of cancers. In this review, MYC regulation and the mechanisms by which MYC adjusts cellular functions and its implication in hematologic malignancies are summarized. Further, we also discuss potential inhibitors of MYC that could be beneficial for treating hematologic malignancies.
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Affiliation(s)
- Seyed Esmaeil Ahmadi
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Samira Rahimi
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Bahman Zarandi
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Rouzbeh Chegeni
- Medical Laboratory Sciences Program, College of Health and Human Sciences, Northern Illinois University, DeKalb, IL, USA.
| | - Majid Safa
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran.
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.
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22
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Mason EF, Hossein-Zadeh Z, Kovach AE. Pediatric hematolymphoid pathology in the gastrointestinal tract. Semin Diagn Pathol 2021; 38:31-37. [PMID: 33863576 DOI: 10.1053/j.semdp.2021.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 02/25/2021] [Accepted: 03/22/2021] [Indexed: 11/11/2022]
Abstract
Hematolymphoid processes involving the gastrointestinal tract in the pediatric and adolescent young adult (AYA) populations include processes occurring primarily within the gastrointestinal tract as well as systemic diseases with predilection for gastrointestinal involvement. Here, we present a focused review of reactive and neoplastic entities occurring in the pediatric and AYA age groups.
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Affiliation(s)
- Emily F Mason
- Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, TN, United States.
| | - Zarrin Hossein-Zadeh
- Department of Pathology, New York University (NYU) Long Island, Winthrop Hospital, Mineola, NY, United States
| | - Alexandra E Kovach
- Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA, United States
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23
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Aresu L, Agnoli C, Nicoletti A, Fanelli A, Martini V, Bertoni F, Marconato L. Phenotypical Characterization and Clinical Outcome of Canine Burkitt-Like Lymphoma. Front Vet Sci 2021; 8:647009. [PMID: 33816589 PMCID: PMC8010238 DOI: 10.3389/fvets.2021.647009] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Accepted: 02/24/2021] [Indexed: 12/20/2022] Open
Abstract
In dogs, Burkitt-like lymphoma (B-LL) is rare tumor and it is classified as a high-grade B-cell malignancy. The diagnosis is challenging because of the similar histologic appearance with other histotypes, no defined phenotypical criteria and poorly described clinical aspects. The aim of the study was to provide a detailed description of clinical and morphological features, as well as immunophenotypical profile of B-LL in comparison with the human counterpart. Thirteen dogs with histologically proven B-LL, for which a complete staging and follow-up were available, were retrospectively selected. Immunohistochemical expression of CD20, PAX5, CD3, CD10, BCL2, BCL6, MYC, and caspase-3 was evaluated. Histologically, all B-LLs showed a diffuse architecture with medium to large-sized cells, high mitotic rate and diffuse starry sky appearance. B-phenotype of neoplastic cells was confirmed both by flow-cytometry and immunohistochemistry. Conversely, B-LLs were negative for BCL2 and MYC, whereas some cases co-expressed BCL6 and CD10, suggesting a germinal center B-cell origin. Disease stage was advanced in the majority of cases. All dogs received CHOP-based chemotherapy with or without immunotherapy. Despite treatment, prognosis was poor, with a median time to progression and survival of 130 and 228 days, respectively. Nevertheless, ~30% of dogs survived more than 1 year. An increased apoptotic index, a high turnover index and caspase-3 index correlated with shorter survival. In conclusion, canine B-LL shows phenotypical differences with the human counterpart along with features that might help to differentiate this entity from diffuse large B-cell lymphoma.
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Affiliation(s)
- Luca Aresu
- Department of Veterinary Sciences, University of Turin, Grugliasco, Italy
| | - Chiara Agnoli
- Department of Medical Veterinary Science, University of Bologna, Bologna, Italy
| | - Arturo Nicoletti
- Department of Veterinary Sciences, University of Turin, Grugliasco, Italy
| | - Antonella Fanelli
- Department of Veterinary Sciences, University of Turin, Grugliasco, Italy
| | - Valeria Martini
- Department of Veterinary Medicine, University of Milan, Lodi, Italy
| | - Francesco Bertoni
- Institute of Oncology Research, Faculty of Biomedical Sciences, University of Italian Switzerland (USI), Bellinzona, Switzerland.,Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
| | - Laura Marconato
- Department of Medical Veterinary Science, University of Bologna, Bologna, Italy
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24
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Huang S, Yasuda T. Pathologically Relevant Mouse Models for Epstein-Barr Virus-Associated B Cell Lymphoma. Front Immunol 2021; 12:639844. [PMID: 33732260 PMCID: PMC7959712 DOI: 10.3389/fimmu.2021.639844] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 02/01/2021] [Indexed: 12/29/2022] Open
Abstract
The Epstein–Barr virus (EBV) is endemic in humans and can efficiently transform infected B cells under some circumstances. If an EBV carrier experiences immune suppression, EBV+ B cells can turn into lymphoblasts and exhibit growth expansion that may cause lymphoproliferative diseases which often develop into lymphoma. Our immune system conducts surveillance for EBV+ B cells in order to block spontaneous tumor formation. Here, we summarize the EBV products involved in tumorigenesis, EBV-associated lymphomas, and pathologically relevant mouse models. Preclinical mouse models for a range of EBV-associated diseases not only clear the path to new therapeutic approaches but also aid in our understanding of the nature of lymphomagenesis and immune surveillance.
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Affiliation(s)
- Shiyu Huang
- Department of Immunology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Tomoharu Yasuda
- Department of Immunology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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25
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Forde S, Matthews JD, Jahangiri L, Lee LC, Prokoph N, Malcolm TIM, Giger OT, Bell N, Blair H, O'Marcaigh A, Smith O, Kenner L, Bomken S, Burke GAA, Turner SD. Paediatric Burkitt lymphoma patient-derived xenografts capture disease characteristics over time and are a model for therapy. Br J Haematol 2021; 192:354-365. [PMID: 32880915 DOI: 10.1111/bjh.17043] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 07/26/2020] [Indexed: 12/28/2022]
Abstract
Burkitt lymphoma (BL) accounts for almost two-thirds of all B-cell non-Hodgkin lymphoma (B-NHL) in children and adolescents and is characterised by a MYC translocation and rapid cell turnover. Intensive chemotherapeutic regimens have been developed in recent decades, including the lymphomes malins B (LMB) protocol, which have resulted in a survival rate in excess of 90%. Recent clinical trials have focused on immunochemotherapy, with the addition of rituximab to chemotherapeutic backbones, showing encouraging results. Despite these advances, relapse and refractory disease occurs in up to 10% of patients and salvage options for these carry a dismal prognosis. Efforts to better understand the molecular and functional characteristics driving relapse and refractory disease may help improve this prognosis. This study has established a paediatric BL patient-derived xenograft (PDX) resource which captures and maintains tumour heterogeneity, may be used to better characterise tumours and identify cell populations responsible for therapy resistance.
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Affiliation(s)
- Sorcha Forde
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge, UK
| | - Jamie D Matthews
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge, UK
| | - Leila Jahangiri
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge, UK.,Department of Life Sciences, Birmingham City University, Birmingham, UK
| | - Liam C Lee
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge, UK
| | - Nina Prokoph
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge, UK
| | - Tim I M Malcolm
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge, UK
| | - Olivier T Giger
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge, UK
| | - Natalie Bell
- Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Helen Blair
- Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | | | - Owen Smith
- Children's Health Ireland at Crumlin, Dublin, Ireland
| | - Lukas Kenner
- Department of Pathology, Medical University of Vienna, Vienna, Austria.,Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, Austria.,Christian Doppler Laboratory for Applied Metabolomics, Vienna, Austria
| | - Simon Bomken
- Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.,The Great North Children's Hospital, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.,Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK
| | - Gladstone A A Burke
- Department of Paediatric Oncology and Haematology, Addenbrooke's Hospital, Cambridge, UK
| | - Suzanne D Turner
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge, UK.,Central European Institute of Technology, Masaryk University, Brno, Czech Republic
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26
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Li J, Zhao S, Zhang W, Jiang Y, Zhu X, Den X, Liu W, Su X. Serous Effusions Diagnostic Accuracy for Hematopoietic Malignancies: A Cyto-Histological Correlation. Front Med (Lausanne) 2020; 7:615080. [PMID: 33344487 PMCID: PMC7744785 DOI: 10.3389/fmed.2020.615080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 11/09/2020] [Indexed: 02/05/2023] Open
Abstract
Background: The aim of this study was to establish the liability of cytological diagnostic and, along with ancillary techniques, to sub-classify hematopoietic malignancies in serous effusions. Methods: We retrospectively reviewed the serous effusions of hematopoietic malignancies over an 11-year period, along with ancillary studies, clinical and histological data. We compared cytological along with histological diagnosis to evaluate the value of cytology itself. Furthermore, the discrepant cases were reviewed. Results: In this study, a total of 242 cases were identified as hematopoietic malignancies. Ancillary technologies were performed: in 24 cases FCM, 242 cases ICC, 35 cases ISH, 81 cases PCR and 10 cases FISH. Cyto-histological correlation was available for 122 cases. The subtyping of hematopoietic malignancies was achieved using cytological material in 65/122 cases (53.3%). Of the 65 cases, T-Acute lymphoblastic leukemia/lymphoma (22.1%) was the leading subtype, followed by Burkitt lymphoma (5.7%), plasmacytoma (5.7%). Cyto-histological correlation showed a 100% concordant rate of diagnosis for hematopoietic malignancies and a high degree of agreement on sub-classification (51.6%). In this regard, T-acute lymphoblastic leukemia/lymphoma, plasmacytoma, extranodal NK/T-cell lymphoma, nasal type, anaplastic large cell lymphoma, myeloid sarcoma, and follicular lymphoma showed the highest degree of agreement (100%). The sub-classification on cytology was achieved in 53 out of the remaining 120 cases without histological diagnosis (44.2%). T-acute lymphoblastic leukemia/lymphoma (20.8%) was again the most frequently encountered subtype, followed by plasmacytoma (5.8%) and Burkitt lymphoma (4.2%). Conclusions: This large series study provided evidence that combining cytology and ancillary studies enabled the accurate serous effusions cytological diagnoses and subsequent sub-classification for the described malignancies.
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Affiliation(s)
- Jinnan Li
- Department of Pathology, West China Hospital of Sichuan University, Chengdu, China
| | - Sha Zhao
- Department of Pathology, West China Hospital of Sichuan University, Chengdu, China
| | - Wenyan Zhang
- Department of Pathology, West China Hospital of Sichuan University, Chengdu, China
| | - Yong Jiang
- Department of Pathology, West China Hospital of Sichuan University, Chengdu, China
| | - Xianglan Zhu
- Department of Pathology, West China Hospital of Sichuan University, Chengdu, China
| | - Xueqin Den
- Department of Pathology, West China Hospital of Sichuan University, Chengdu, China
| | - Weiping Liu
- Department of Pathology, West China Hospital of Sichuan University, Chengdu, China
| | - Xueying Su
- Department of Pathology, West China Hospital of Sichuan University, Chengdu, China
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27
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[Fluorescence in situ hybridization in the diagnosis of aggressive B-cell lymphomas]. DER PATHOLOGE 2020; 41:574-581. [PMID: 32909092 DOI: 10.1007/s00292-020-00816-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
The introduction of new lymphoma entities that are defined by chromosomal rearrangements has led to changes concerning the diagnostic algorithms in routine hematopathology, particularly for the large group of aggressive B‑cell lymphomas. The new, genetically defined entity high-grade B‑cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (double/triple hit lymphoma) is morphologically heterogenous and comprises lymphomas with the morphology of a diffuse large B‑cell lymphoma (DLBCL), but also cases with blastoid appearance as well as intermediate/Burkitt-like morphology. This implies a cytogenetic analysis for the final classification of aggressive lymphomas with DLBCL morphology, which constitute the most common lymphomas in daily practice. This analysis is currently most efficiently performed via a sequential fluorescence in situ hybridization (FISH) approach, with an initial MYC-FISH, that is followed (if required, i.e., if a MYC rearrangement is detected) by an analysis regarding a BCL2- and BCL6-chromosomal rearrangement. In addition, the update of the fourth edition of the WHO classification for hematopoietic neoplasms introduced additional lymphoma subgroups that are defined by chromosomal rearrangements, such as Burkitt-like lymphoma with 11q aberration as well as large B cell lymphoma with IRF4 rearrangement. Therefore, FISH currently plays an important role in the diagnostic armamentarium in routine diagnostic hematopathology.
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28
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Kasparian S, Burns E, Shehabeldin A, Awar M, Pingali SR. Recurrent small bowel obstruction caused by Burkitt lymphoma in an elderly man: a case report and review of the literature. J Med Case Rep 2020; 14:127. [PMID: 32782017 PMCID: PMC7422579 DOI: 10.1186/s13256-020-02449-y] [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: 06/01/2019] [Accepted: 07/07/2020] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Acute small bowel obstruction is a common surgical emergency usually caused by abdominal adhesions, followed by intraluminal tumors from metastatic disease. Although lymphomas have been known to cause bowel obstruction, Burkitt lymphoma is seldom reported to induce an obstruction in the adult population. CASE PRESENTATION A 78-year-old Hispanic man with a history of abdominal interventions presented to our hospital with abdominal pain. Computed tomography revealed a partial small bowel obstruction attributed to local inflammation or adhesions. Medical management with bowel rest and nasogastric decompression resulted in resolution of symptoms and quick discharge. He returned 2 days later with worsening abdominal pain. Repeat imaging showed progression of the partial small bowel obstruction, but with an additional 1.6-cm nodular density abutting the anterior aspect of the gastric antrum and lobulated anterior gastric antral wall thickening. He was taken to the operating room, where several masses were found. Intraoperative frozen sections were consistent with lymphoma, and pathology later revealed Burkitt lymphoma. Disease was found on both sides of the diaphragm by positron emission tomography. After the initial resection and adjuvant chemotherapy, the patient is alive and well about 14 months after resection. CONCLUSIONS Small bowel obstruction is uncommonly due to Burkitt lymphoma in the geriatric population and is more frequently seen in the pediatric and young adult populations. Burkitt lymphoma is very aggressive with rapid cell turnover leading to significant morbidity. The rapid recurrence of an acute abdominal process should prompt an investigation for a more sinister cause such as malignancy.
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Affiliation(s)
- Saro Kasparian
- Department of Internal Medicine, Houston Methodist Hospital, Houston, TX, 77030, USA.
| | - Ethan Burns
- Department of Internal Medicine, Houston Methodist Hospital, Houston, TX, 77030, USA
| | - Ahmed Shehabeldin
- Department of Pathology, Houston Methodist Hospital, Houston, TX, 77030, USA
| | - Melina Awar
- Department of Internal Medicine, Houston Methodist Hospital, Houston, TX, 77030, USA
| | - Sai Ravi Pingali
- Department of Internal Medicine, Houston Methodist Hospital, Houston, TX, 77030, USA.,Division of Hematology and Oncology, Houston Methodist Hospital, Houston, TX, 77030, USA
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29
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Yumimoto K, Nakayama KI. Recent insight into the role of FBXW7 as a tumor suppressor. Semin Cancer Biol 2020; 67:1-15. [PMID: 32113998 DOI: 10.1016/j.semcancer.2020.02.017] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 02/15/2020] [Accepted: 02/26/2020] [Indexed: 12/12/2022]
Abstract
FBXW7 (also known as Fbw7, Sel10, hCDC4, or hAgo) is a tumor suppressor and the most frequently mutated member of the F-box protein family in human cancers. FBXW7 functions as the substrate recognition component of an SCF-type E3 ubiquitin ligase. It specifically controls the proteasome-mediated degradation of many oncoproteins such as c-MYC, NOTCH, KLF5, cyclin E, c-JUN, and MCL1. In this review, we summarize the molecular and biological features of FBXW7 and its substrates as well as the impact of mutations of FBXW7 on cancer development. We also address the clinical potential of anticancer therapy targeting FBXW7.
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Affiliation(s)
- Kanae Yumimoto
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka, 812-8582, Japan
| | - Keiichi I Nakayama
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka, 812-8582, Japan.
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30
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Mimery AH, Jabbour J, Sykes B, MacDermid E, Al-Askari M, De Clercq S. Burkitt Leukemia Presenting as Acute Appendicitis: A Case Report and Literature Review. AMERICAN JOURNAL OF CASE REPORTS 2020; 21:e921568. [PMID: 32094318 PMCID: PMC7038641 DOI: 10.12659/ajcr.921568] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Patient: Female, 6-year-old Final Diagnosis: Burkitt’s leukemia Symptoms: Right iliac fossa pain Medication: — Clinical Procedure: Laparoscopic cecectomy Specialty: Surgery
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Affiliation(s)
- Alexander H Mimery
- Department of Surgery, Gladstone Hospital, Gladstone, Queensland, Australia
| | - Joe Jabbour
- Department of Surgery, Gladstone Hospital, Gladstone, Queensland, Australia
| | - Blake Sykes
- Department of Surgery, Gladstone Hospital, Gladstone, Queensland, Australia
| | - Ewan MacDermid
- Department of Colorectal Surgery, Royal North Shore Hospital, Sydney, New South Wales, Australia
| | - Mohamed Al-Askari
- Department of Surgery, Gladstone Hospital, Gladstone, Queensland, Australia
| | - Stefaan De Clercq
- Department of Surgery, Gladstone Hospital, Gladstone, Queensland, Australia
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31
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Ndede I, Mining SK, Patel K, Wanjala FM, Tenge C. Immunoglobulin heavy variable (IgHV) gene mutation and micro-RNA expression in Burkitt's lymphoma at Moi Teaching and Referral Hospital in Western Kenya. Afr Health Sci 2019; 19:3242-3248. [PMID: 32127902 PMCID: PMC7040314 DOI: 10.4314/ahs.v19i4.48] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
INTRODUCTION Burkitt's lymphoma (BL) is a virus associated childhood B-cell cancer common in Eastern Africa. Continued survival of B-cells in germinal centres depend on expression of high affinity immunoglobulins (Ig) to complementary antigens by somatic hypermutation of Ig genes. Cellular microRNAs, non-coding RNAs have been reported to play role in cell cycle regulation. Both viral antigen dependent mutation and micro-RNA expression maybe involved in BL pathogenesis. OBJECTIVE To describe immunoglobulin heavy variable (IgHV) rearrangement and micro-RNA expressions in BL tumours. METHODS Genomic DNA were extracted and purified from BL tissue blocks at Moi Teaching and Referral Hospital, before amplification using IgHV consensus primers and sequencing. The sequences were then aligned with germline alleles in IMGT/V-QUEST® database. Total RNA extracted from tissue blocks and cell lines were used to determine relative expression of hsamiR-34a and hsa-miR-127. RESULTS In all tumours, allele alignment scores and number of mutations range were 89.2-93.2%, 15-24 respectively. The range of IgHV amino acid changes were higher in EBER-1+ (15-25) than EBER-1- (9-15). In MYC+ tumours, the relative expression were: hsa-miR-127(2.09);hsa-miR-34a (2.8) and MYC- hsa-miR-127 (1.2), hsa-miR-34a (1.0). CONCLUSION B-cell in BL contained somatic mutated IgHV gene and upregulated cellular microRNAs with possible pathogenetic role(s).
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Affiliation(s)
- Isaac Ndede
- Department of Immunology, Moi University School of Medicine, Eldoret, Kenya
- Department of Biological Sciences, University of Eldoret, Eldoret, Kenya
| | - SK Mining
- Department of Immunology, Moi University School of Medicine, Eldoret, Kenya
| | - K Patel
- Department of Immunology, Moi University School of Medicine, Eldoret, Kenya
| | - FM Wanjala
- Department of Biological Sciences, University of Eldoret, Eldoret, Kenya
| | - C Tenge
- Department of Child Health and Paediatrics, Moi University School of Medicine, Eldoret, Kenya
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32
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Burkitt's Lymphoma of the Base of the Tongue: A Case Report and Review of the Literature. EAR, NOSE & THROAT JOURNAL 2019. [DOI: 10.1177/014556130708600617] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Burkitt's lymphoma is a highly aggressive, mature B cell non-Hodgkin's lymphoma that is rare outside Africa. We report a case of Burkitt's lymphoma presenting as a rapidly expanding tongue-base mass that caused airway obstruction in an 80-year-old Palestinian man living in California. According to our review of the literature, this is only the third reported case of Burkitt's lymphoma arising in the base of the tongue. We also discuss the incidence, epidemiology, genetics, prognosis, and treatment of this malignancy. Because Burkitt's lymphoma is one of the fastest-growing tumors in humans, rapid diagnosis and treatment are important. Treatment involves brief-duration, high-intensity chemotherapy and central nervous system prophylaxis. It is important for the otolaryngologist to recognize this disease and to understand the steps necessary to treat this aggressive tumor.
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33
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Liu Y, Bian T, Zhang Y, Zheng Y, Zhang J, Zhou X, Xie J. A combination of LMO2 negative and CD38 positive is useful for the diagnosis of Burkitt lymphoma. Diagn Pathol 2019; 14:100. [PMID: 31484540 PMCID: PMC6727582 DOI: 10.1186/s13000-019-0876-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Accepted: 08/23/2019] [Indexed: 12/05/2022] Open
Abstract
Background To evaluate the clinical utility of LIM Domain Only 2 (LMO2) negative and CD38 positive in diagnosis of Burkitt lymphoma (BL). Methods LMO2 and CD38 expression determined by immunohistochemistry in 75 BL, 12 High-grade B-cell lymphoma, NOS (HGBL,NOS) and 3 Burkitt-like lymphomas with the 11q aberration. Results The sensitivity and specificity of LMO2 negative for detecting BL were 98.67 and 100%, respectively; those of CD38 positive were 98.67 and 66.67%, respectively. The sensitivity and specificity of a combination of both for detecting BL were 97.33 and 100%, respectively. In our study, the combined LMO2 negative and CD38 positive results had a higher area under the curve than either LMO2 negative or CD38 positive alone. Conclusions A combination of LMO2 negative and CD38 positive is useful for the diagnosis of Burkitt lymphoma.
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Affiliation(s)
- Yifei Liu
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, 226001, People's Republic of China
| | - Tingting Bian
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, 226001, People's Republic of China
| | - Yanlin Zhang
- Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100000, People's Republic of China
| | - Yuanyuan Zheng
- Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100000, People's Republic of China
| | - Jianguo Zhang
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, 226001, People's Republic of China
| | - Xiaoge Zhou
- Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100000, People's Republic of China.
| | - Jianlan Xie
- Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100000, People's Republic of China.
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34
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Li J, Zhang W, Zhao S, Jiang Y, Liu W, Zhu X, Su X. The accuracy of diagnosing Burkitt lymphoma in serous effusion specimen: A cytological‐histological correlation with ancillary studies. Cytopathology 2019; 30:378-384. [PMID: 30983044 DOI: 10.1111/cyt.12707] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 04/09/2019] [Accepted: 04/10/2019] [Indexed: 02/05/2023]
Affiliation(s)
- Jinnan Li
- Department of Pathology West China Hospital of Sichuan University Chengdu China
| | - Wenyan Zhang
- Department of Pathology West China Hospital of Sichuan University Chengdu China
| | - Sha Zhao
- Department of Pathology West China Hospital of Sichuan University Chengdu China
| | - Yong Jiang
- Department of Pathology West China Hospital of Sichuan University Chengdu China
| | - Weiping Liu
- Department of Pathology West China Hospital of Sichuan University Chengdu China
| | - Xianglan Zhu
- Department of Pathology West China Hospital of Sichuan University Chengdu China
| | - Xueying Su
- Department of Pathology West China Hospital of Sichuan University Chengdu China
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35
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Umek T, Sollander K, Bergquist H, Wengel J, Lundin KE, Smith CIE, Zain R. Oligonucleotide Binding to Non-B-DNA in MYC. Molecules 2019; 24:E1000. [PMID: 30871121 PMCID: PMC6429085 DOI: 10.3390/molecules24051000] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Revised: 02/25/2019] [Accepted: 03/06/2019] [Indexed: 11/16/2022] Open
Abstract
MYC, originally named c-myc, is an oncogene deregulated in many different forms of cancer. Translocation of the MYC gene to an immunoglobulin gene leads to an overexpression and the development of Burkitt's lymphoma (BL). Sporadic BL constitutes one subgroup where one of the translocation sites is located at the 5'-vicinity of the two major MYC promoters P₁ and P₂. A non-B-DNA forming sequence within this region has been reported with the ability to form an intramolecular triplex (H-DNA) or a G-quadruplex. We have examined triplex formation at this site first by using a 17 bp triplex-forming oligonucleotide (TFO) and a double strand DNA (dsDNA) target corresponding to the MYC sequence. An antiparallel purine-motif triplex was detected using electrophoretic mobility shift assay. Furthermore, we probed for H-DNA formation using the BQQ-OP based triplex-specific cleavage assay, which indicated the formation of the structure in the supercoiled plasmid containing the corresponding region of the MYC promoter. Targeting non-B-DNA structures has therapeutic potential; therefore, we investigated their influence on strand-invasion of anti-gene oligonucleotides (ON)s. We show that in vitro, non-B-DNA formation at the vicinity of the ON target site facilitates dsDNA strand-invasion of the anti-gene ONs.
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Affiliation(s)
- Tea Umek
- Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Karolinska University Hospital Huddinge, 141 86 Huddinge, Sweden.
| | - Karin Sollander
- Department of Molecular Biology and Functional Genomics, Stockholm University, 171 65 Stockholm, Sweden.
| | - Helen Bergquist
- Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Karolinska University Hospital Huddinge, 141 86 Huddinge, Sweden.
| | - Jesper Wengel
- Biomolecular Nanoscale Engineerng Center, Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, M5230 Odense, Denmark.
| | - Karin E Lundin
- Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Karolinska University Hospital Huddinge, 141 86 Huddinge, Sweden.
| | - C I Edvard Smith
- Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Karolinska University Hospital Huddinge, 141 86 Huddinge, Sweden.
| | - Rula Zain
- Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Karolinska University Hospital Huddinge, 141 86 Huddinge, Sweden.
- Department of Clinical Genetics, Centre for Rare Diseases, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
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Abstract
Over the last decade, advancements in massively-parallel DNA sequencing and computational biology have allowed for unprecedented insights into the fundamental mutational processes that underlie virtually every major cancer type. Two major cancer genomics consortia-The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC)-have produced rich databases of mutational, pathological, and clinical data that can be mined through web-based portals, allowing for correlative studies and testing of novel hypotheses on well-powered patient cohorts.In this chapter, we will review the impact of these technological developments on the understanding of molecular subtypes that promote prostate cancer initiation, progression, metastasis, and clinical aggression. In particular, we will focus on molecular subtypes that define clinically-relevant patient cohorts and assess how a better understanding of how these subtypes-in both somatic and germline genomes-may influence the clinical course for individual men diagnosed with prostate cancer.
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Targeting the MYC Oncogene in Burkitt Lymphoma through HSP90 Inhibition. Cancers (Basel) 2018; 10:cancers10110448. [PMID: 30453475 PMCID: PMC6266960 DOI: 10.3390/cancers10110448] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Revised: 11/13/2018] [Accepted: 11/14/2018] [Indexed: 02/07/2023] Open
Abstract
Overexpression of the MYC oncogene is a key feature of many human malignancies including Burkitt lymphoma. While MYC is widely regarded to be a promising therapeutic target, a clinically effective MYC inhibitor is still elusive. Here, we report an alternative strategy, targeting MYC indirectly through inhibition of the HSP90 machinery. We found that inhibition of HSP90 function reduces MYC expression in human Burkitt lymphoma through suppression of MYC transcription and destabilization of MYC protein, thereby diminishing the proliferation of tumor cells. Consistently, treatment of Burkitt lymphoma cell lines with HSP90 inhibitors (17-AAG or 17-DMAG) was accompanied by downregulation of canonical MYC target genes. Combination treatment with 17-DMAG and the proteasome inhibitor, MG-132, led to accumulation of MYC protein, indicating that upon HSP90 inhibition, MYC is degraded by the proteasome. Using co-immunoprecipitation, we furthermore demonstrated a direct interaction between MYC and HSP90, indicating that MYC is an HSP90 client protein in Burkitt lymphoma. Together, we report here the use of HSP90 inhibitors as an alternative approach to target the MYC oncogene and its network in Burkitt lymphoma.
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Kim SE, Jung Y, Oh TH, Kim UJ, Kang SJ, Jang HC, Park KH, Lee KH, Jung SI. Case report: dual primary AIDS-defining cancers in an HIV-infected patient receiving antiretroviral therapy: Burkitt's lymphoma and Kaposi's sarcoma. BMC Cancer 2018; 18:1080. [PMID: 30409111 PMCID: PMC6225729 DOI: 10.1186/s12885-018-5019-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Accepted: 10/31/2018] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The incidence of AIDS-defining cancers (ADCs) has decreased markedly in the era of highly active antiretroviral therapy (HAART). The occurrence of two ADCs is rare in people living with HIV or AIDS (PWHA) who are severely immunosuppressed or have incomplete virologic suppression. CASE PRESENTATION We report a case of dual primary ADCs, especially NHL followed by KS, in a 70-year-old HIV-infected man who was on antiretroviral therapy and had successful virologic suppression. During HAART, he presented with generalized myalgia and abdominal pain. Multiple liver masses were detected and a biopsy revealed Burkitt's lymphoma. After three cycles of anticancer chemotherapy with a favorable response, he was diagnosed with cytomegalovirus retinitis and the anti-cancer chemotherapy was discontinued. Despite successful virologic suppression with HAART, human herpes virus-8 associated Kaposi's sarcoma was diagnosed in his right thigh. He underwent radiation therapy. CONCLUSION These findings suggest that multiple ADCs can occur in PWHA who are receiving HAART and have successful virologic suppression. Healthcare providers caring for PWHA should maintain vigilance for the development of a broad spectrum of cancers.
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Affiliation(s)
- Seong Eun Kim
- Department of Infectious Diseases, Chonnam National University Medical School, 42, Jebong Ro, Donggu, Gwangju, 61469 Korea
| | - Younggon Jung
- Department of Infectious Diseases, Chonnam National University Medical School, 42, Jebong Ro, Donggu, Gwangju, 61469 Korea
| | - Tae Hoon Oh
- Department of Infectious Diseases, Chonnam National University Medical School, 42, Jebong Ro, Donggu, Gwangju, 61469 Korea
| | - Uh Jin Kim
- Department of Infectious Diseases, Chonnam National University Medical School, 42, Jebong Ro, Donggu, Gwangju, 61469 Korea
| | - Seung-Ji Kang
- Department of Infectious Diseases, Chonnam National University Medical School, 42, Jebong Ro, Donggu, Gwangju, 61469 Korea
| | - Hee-Chang Jang
- Department of Infectious Diseases, Chonnam National University Medical School, 42, Jebong Ro, Donggu, Gwangju, 61469 Korea
| | - Kyung-Hwa Park
- Department of Infectious Diseases, Chonnam National University Medical School, 42, Jebong Ro, Donggu, Gwangju, 61469 Korea
| | - Kyung-Hwa Lee
- Department of Pathology, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Sook In Jung
- Department of Infectious Diseases, Chonnam National University Medical School, 42, Jebong Ro, Donggu, Gwangju, 61469 Korea
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Ejaz K, Khan QA, Raza MA, Ahmed RS, Aleem A. High-grade Burkitt Lymphoma Presenting as a Buttock Mass and Foot Drop. Cureus 2018; 10:e3368. [PMID: 30510878 PMCID: PMC6257518 DOI: 10.7759/cureus.3368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Burkitt lymphoma (BL), a highly aggressive B-cell non-Hodgkin lymphoma (NHL), usually presents in children and young adults with large extranodal masses involving jaw bones, gastrointestinal tract, and central nervous system. The three main subtypes of BL are endemic, sporadic, and immunodeficiency variant. Extranodal involvement is common in each variant of BL, although muscle tissue involvement is distinctly rare. Mode of spread may be hematogenous or via direct extension of the primary tumor. In this report, we present a case of a 41-year-old male who presented with a palpable mass in the buttock leading to foot drop as the initial manifestation of BL. An exhaustive review of the literature failed to discover any previous reports of BL occurring in this location.
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Affiliation(s)
- Komal Ejaz
- Intrenal Medicine, Sheikh Zayed Hospital, Lahore, PAK
| | - Qalb A Khan
- Internal Medicine, Wellspan Good Samaritan Hospital, Lebanon, USA
| | - Muhammad A Raza
- Internal Medicine, Jinnah Hospital Lahore/Allama Iqbal Medical College, Lahore, PAK
| | - Roy Sonia Ahmed
- Internal Medicine, Quaid-E-Azam Medical College, Bahawalpur, PAK
| | - Abdul Aleem
- Internal Medicine, St. Mary Mercy Hospital, Livonia, USA
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Carvalho de Oliveira J, Molinari Roberto G, Baroni M, Bezerra Salomão K, Alejandra Pezuk J, Sol Brassesco M. MiRNA Dysregulation in Childhood Hematological Cancer. Int J Mol Sci 2018; 19:ijms19092688. [PMID: 30201877 PMCID: PMC6165337 DOI: 10.3390/ijms19092688] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Revised: 09/03/2018] [Accepted: 09/08/2018] [Indexed: 12/14/2022] Open
Abstract
For decades, cancer biology focused largely on the protein-encoding genes that have clear roles in tumor development or progression: cell-cycle control, apoptotic evasion, genome instability, drug resistance, or signaling pathways that stimulate growth, angiogenesis, or metastasis. MicroRNAs (miRNAs), however, represent one of the more abundant classes of cell modulators in multicellular organisms and largely contribute to regulating gene expression. Many of the ~2500 miRNAs discovered to date in humans regulate vital biological processes, and their aberrant expression results in pathological and malignant outcomes. In this review, we highlight what has been learned about the roles of miRNAs in some of the most common human pediatric leukemias and lymphomas, along with their value as diagnostic/prognostic factors.
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Affiliation(s)
| | - Gabriela Molinari Roberto
- Department of Pediatrics, Ribeirão Preto School of Medicine, University of São Paulo, 14049-900 Ribeirão Preto, Brazil.
| | - Mirella Baroni
- Department of Pediatrics, Ribeirão Preto School of Medicine, University of São Paulo, 14049-900 Ribeirão Preto, Brazil.
| | - Karina Bezerra Salomão
- Department of Pediatrics, Ribeirão Preto School of Medicine, University of São Paulo, 14049-900 Ribeirão Preto, Brazil.
| | - Julia Alejandra Pezuk
- Programa de Pós-graduação em Farmácia, Anhanguera University of São Paulo, UNIAN/SP, 05145-200 São Paulo, Brazil.
| | - María Sol Brassesco
- Departamento de Biologia, Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo, 14040-901 Ribeirão Preto, Brazil.
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Burkitt lymphoma- a rare but challenging lymphoma. Best Pract Res Clin Haematol 2018; 31:279-284. [PMID: 30213397 DOI: 10.1016/j.beha.2018.07.013] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Accepted: 07/20/2018] [Indexed: 10/28/2022]
Abstract
Burkitt lymphoma (BL) is a rare, aggressive subtype of non-Hodgkin lymphoma affecting approximately 1500 patients per year. Three forms of BL exist (sporadic, endemic, immunodeficiency associated) and the endemic form was first discovered as being driven by the Epstein Barr virus in areas of the world where malaria is prevalent. BL has the characteristic t8; 14 cytogenetic translocation that leads to constitutive activation of the MYC gene, which drives BL cell division. Therapy of BL has resulted in cure for many patients but significant toxicity and treatment related complications remains problematic in the approach to BL therapy. Treatment options for relapsed and refractory disease remain limited however novel treatments are being studied to block MYC activation, and cold lead to promising options for patients with relapsed and refractory disease.
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Jiménez-P R, Martín-Cortázar C, Kourani O, Chiodo Y, Cordoba R, Domínguez-Franjo MP, Redondo JM, Iglesias T, Campanero MR. CDCA7 is a critical mediator of lymphomagenesis that selectively regulates anchorage-independent growth. Haematologica 2018; 103:1669-1678. [PMID: 29880607 PMCID: PMC6165795 DOI: 10.3324/haematol.2018.188961] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Accepted: 06/04/2018] [Indexed: 11/09/2022] Open
Abstract
Tumor formation involves the acquisition of numerous capacities along the progression from a normal cell into a malignant cell, including limitless proliferation (immortalization) and anchorage-independent growth, a capacity that correlates extremely well with tumorigenesis. Great efforts have been made to uncover genes involved in tumor formation, but most genes identified participate in processes related to cell proliferation. Accordingly, therapies targeting these genes also affect the proliferation of normal cells. To identify potential targets for therapeutic intervention more specific to tumor cells, we looked for genes implicated in the acquisition of anchorage-independent growth and in vivo tumorigenesis capacity. A transcriptomic analysis identified CDCA7 as a candidate gene. Indeed, CDCA7 protein was upregulated in Burkitt's lymphoma cell lines and human tumor biopsy specimens relative to control cell lines and tissues, respectively. CDCA7 levels were also markedly elevated in numerous T and B-lymphoid tumor cell lines. While CDCA7 was not required for anchorage-dependent growth of normal fibroblasts or non-malignant lymphocytes, it was essential but not sufficient for anchorage-independent growth of lymphoid tumor cells and for lymphomagenesis. These data suggest that therapies aimed at inhibiting CDCA7 expression or function might significantly decrease the growth of lymphoid tumors.
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Affiliation(s)
- Raúl Jiménez-P
- Department of Cancer Biology, Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain
| | - Carla Martín-Cortázar
- Department of Cancer Biology, Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain
| | - Omar Kourani
- Department of Cancer Biology, Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain
| | - Yuri Chiodo
- Department of Cancer Biology, Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain
| | - Raul Cordoba
- Department of Hematology, University Hospital Infanta Sofía, San Sebastián de los Reyes, Madrid, Spain
| | | | - Juan Miguel Redondo
- Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares, (CNIC), Madrid, Spain.,CIBERCV, Spain
| | - Teresa Iglesias
- Department of Endocrine and Nervous Systems Pathophysiology, Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Miguel R Campanero
- Department of Cancer Biology, Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain .,CIBERCV, Spain
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Yang Y, Xue K, Li Z, Zheng W, Dong W, Song J, Sun S, Ma T, Li W. c-Myc regulates the CDK1/cyclin B1 dependent‑G2/M cell cycle progression by histone H4 acetylation in Raji cells. Int J Mol Med 2018; 41:3366-3378. [PMID: 29512702 PMCID: PMC5881754 DOI: 10.3892/ijmm.2018.3519] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Accepted: 02/08/2018] [Indexed: 01/11/2023] Open
Abstract
Overexpression of c-Myc is involved in the tumorigenesis of B-lineage acute lymphoblastic leukemia (B‑ALL), but the mechanism is not well understood. In the present study, a c‑Myc‑knockdown model (Raji‑KD) was established using Raji cells, and it was indicated that c‑Myc regulates the expression of genes associated with cell cycle progression in G2/M‑phase, cyclin D kinase (CDK)1 and cyclin B1, by modulating 60 kDa Tat‑interactive protein (TIP60)/males absent on the first (MOF)‑mediated histone H4 acetylation (AcH4), which was then completely restored by re‑introduction of the c‑Myc gene into the Raji‑KD cells. The expression of CDK1 and cyclin B1 was markedly suppressed in Raji‑KD cells, resulting in G2/M arrest. In comparison to Raji cells, the proliferation of Raji‑KD cells was significantly reduced, and it was recovered via re‑introduction of the c‑Myc gene. In the tumorigenesis assays, the loss of c‑Myc expression significantly suppressed Raji cell‑derived lymphoblastic tumor formation. Although c‑Myc also promotes Raji cell apoptosis via the caspase‑3‑associated pathway, CDK1/cyclin B1‑dependent‑G2/M cell cycle progression remains the major driving force of c‑Myc‑controlled tumorigenesis. The present results suggested that c‑Myc regulates cyclin B1‑ and CDK1‑dependent G2/M cell cycle progression by TIP60/MOF-mediated AcH4 in Raji cells.
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Affiliation(s)
- Yan Yang
- Department of Biological Chemistry, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Kai Xue
- Department of Biological Chemistry, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Zhi Li
- Department of Clinical Laboratory, Dalian Municipal Central Hospital Affiliated to Dalian Medical University, Dalian, Liaoning 116033, P.R. China
| | - Wei Zheng
- Department of Clinical Laboratory, Dalian Municipal Central Hospital Affiliated to Dalian Medical University, Dalian, Liaoning 116033, P.R. China
| | - Weijie Dong
- Department of Biological Chemistry, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Jiazhe Song
- Department of Biological Chemistry, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Shijie Sun
- Department of Biological Chemistry, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Tonghui Ma
- Department of Biological Chemistry, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Wenzhe Li
- Department of Biological Chemistry, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
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Siddiqui MA, Sartaj S, Ali Rizvi SW, Khan IA. Ovarian Torsion as an Unusual Presentation of Primary Bilateral Ovarian Lymphoma. Indian J Med Paediatr Oncol 2018. [DOI: 10.4103/ijmpo.ijmpo_68_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
AbstractPrimary ovarian involvement by Burkitt's lymphoma is rare and accounts for 0.5% of nonHodgkin lymphoma and 1.5% of ovarian tumors. We herein describe a very rare case of primary bilateral ovarian lymphoma in a 14-year-old presenting as ovarian torsion.
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Affiliation(s)
| | - Sara Sartaj
- Department of Medical Student, Jawaharlal Nehru Medical College, Aligarh, Uttar Pradesh, India
| | - Syed Wajahat Ali Rizvi
- Department of Ophtalmology, Jawaharlal Nehru Medical College, Aligarh, Uttar Pradesh, India
| | - Iraj Alam Khan
- Department of Pediatrics, Jawaharlal Nehru Medical College, Aligarh, Uttar Pradesh, India
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45
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Bhoopalan SV, Das S. Case 3: Increased Snoring in a 7-year-old Boy. Pediatr Rev 2017; 38:569. [PMID: 29196514 DOI: 10.1542/pir.2016-0039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Affiliation(s)
| | - Samrat Das
- Department of Pediatrics, University of Nevada Las Vegas, Las Vegas, NV
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46
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Oduor CI, Kaymaz Y, Chelimo K, Otieno JA, Ong’echa JM, Moormann AM, Bailey JA. Integrative microRNA and mRNA deep-sequencing expression profiling in endemic Burkitt lymphoma. BMC Cancer 2017; 17:761. [PMID: 29132323 PMCID: PMC5683570 DOI: 10.1186/s12885-017-3711-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2017] [Accepted: 10/30/2017] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Burkitt lymphoma (BL) is characterized by overexpression of the c-myc oncogene, which in the vast majority of cases is a consequence of an IGH/MYC translocation. While myc is the seminal event, BL is a complex amalgam of genetic and epigenetic changes causing dysregulation of both coding and non-coding transcripts. Emerging evidence suggest that abnormal modulation of mRNA transcription via miRNAs might be a significant factor in lymphomagenesis. However, the alterations in these miRNAs and their correlations to their putative mRNA targets have not been extensively studied relative to normal germinal center (GC) B cells. METHODS Using more sensitive and specific transcriptome deep sequencing, we compared previously published small miRNA and long mRNA of a set of GC B cells and eBL tumors. MiRWalk2.0 was used to identify the validated target genes for the deregulated miRNAs, which would be important for understanding the regulatory networks associated with eBL development. RESULTS We found 211 differentially expressed (DE) genes (79 upregulated and 132 downregulated) and 49 DE miRNAs (22 up-regulated and 27 down-regulated). Gene Set enrichment analysis identified the enrichment of a set of MYC regulated genes. Network propagation-based method and correlated miRNA-mRNA expression analysis identified dysregulated miRNAs, including miR-17~95 cluster members and their target genes, which have diverse oncogenic properties to be critical to eBL lymphomagenesis. Central to all these findings, we observed the downregulation of ATM and NLK genes, which represent important regulators in response to DNA damage in eBL tumor cells. These tumor suppressors were targeted by multiple upregulated miRNAs (miR-19b-3p, miR-26a-5p, miR-30b-5p, miR-92a-5p and miR-27b-3p) which could account for their aberrant expression in eBL. CONCLUSION Combined loss of p53 induction and function due to miRNA-mediated regulation of ATM and NLK, together with the upregulation of TFAP4, may be a central role for human miRNAs in eBL oncogenesis. This facilitates survival of eBL tumor cells with the IGH/MYC chromosomal translocation and promotes MYC-induced cell cycle progression, initiating eBL lymphomagenesis. This characterization of miRNA-mRNA interactions in eBL relative to GC B cells provides new insights on miRNA-mediated transcript regulation in eBL, which are potentially useful for new improved therapeutic strategies.
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Affiliation(s)
- Cliff I. Oduor
- Center for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya
- Department of Biomedical Sciences and Technology, Maseno University, Maseno, Kenya
| | - Yasin Kaymaz
- Department of Bioinformatics & Integrative Biology, University of Massachusetts Medical School, Worcester, MA USA
| | - Kiprotich Chelimo
- Department of Biomedical Sciences and Technology, Maseno University, Maseno, Kenya
| | - Juliana A. Otieno
- Jaramogi Oginga Odinga Teaching and Referral Hospital, Ministry of Health, Kisumu, Kenya
| | | | - Ann M. Moormann
- Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, MA USA
| | - Jeffrey A. Bailey
- Department of Bioinformatics & Integrative Biology, University of Massachusetts Medical School, Worcester, MA USA
- Division of Transfusion Medicine, Department of Medicine, University of Massachusetts Medical School, 368 Plantation St. Albert Sherman Building 41077, Worcester, MA 01605 USA
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Oduor CI, Movassagh M, Kaymaz Y, Chelimo K, Otieno J, Ong'echa JM, Moormann AM, Bailey JA. Human and Epstein-Barr Virus miRNA Profiling as Predictive Biomarkers for Endemic Burkitt Lymphoma. Front Microbiol 2017; 8:501. [PMID: 28400759 PMCID: PMC5368269 DOI: 10.3389/fmicb.2017.00501] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2016] [Accepted: 03/10/2017] [Indexed: 11/17/2022] Open
Abstract
Endemic Burkitt lymphoma (eBL) is an aggressive B cell lymphoma and is associated with Epstein-Barr virus (EBV) and Plasmodium falciparum malaria co-infections. Central to BL oncogenesis is the over-expression of the MYC proto-oncogene which is caused by a translocation of an Ig enhancer in approximation to the myc gene. While whole genome/transcriptome sequencing methods have been used to define driver mutations and transcriptional dysregulation, microRNA (miRNA) dysregulation and differential expression has yet to be fully characterized. We hypothesized that both human and EBV miRNAs contribute to eBL clinical presentation, disease progression, and poor outcomes. Using sensitive and precise deep sequencing, we identified miRNAs from 17 Kenyan eBL patient tumor samples and delineated the complement of both host and EBV miRNAs. One human miRNA, hsa-miR-10a-5p was found to be differentially expressed (DE), being down-regulated in jaw tumors relative to abdominal and in non-survivors compared to survivors. We also examined EBV miRNAs, which made up 2.7% of the miRNA composition in the eBL samples. However, we did not find any significant associations regarding initial patient outcome or anatomical presentation. Gene ontology analysis and pathway enrichment of previously validated targets of miR-10a-5p suggest that it can promote tumor cell survival as well as aid in evasion of apoptosis. To examine miR-10a-5p regulatory effect on gene expression in eBL, we performed a pairwise correlation coefficient analysis on the expression levels of all its validated targets. We found a significant enrichment of correlated target genes consistent with miR-10a-5p impacting expression. The functions of genes and their correlation fit with multiple target genes impacting tumor resilience. The observed downregulation of miR-10a and associated genes suggests a role for miRNA in eBL patient outcomes and has potential as a predictive biomarker that warrants further investigation.
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Affiliation(s)
- Cliff I Oduor
- Center for Global Health Research, Kenya Medical Research InstituteKisumu, Kenya; Department of Biomedical Sciences and Technology, Maseno UniversityMaseno, Kenya
| | - Mercedeh Movassagh
- Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School Worcester, MA, USA
| | - Yasin Kaymaz
- Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School Worcester, MA, USA
| | - Kiprotich Chelimo
- Department of Biomedical Sciences and Technology, Maseno University Maseno, Kenya
| | - Juliana Otieno
- Jaramogi Oginga Odinga Teaching and Referral Hospital, Ministry of Medical Services Kisumu, Kenya
| | - John M Ong'echa
- Center for Global Health Research, Kenya Medical Research Institute Kisumu, Kenya
| | - Ann M Moormann
- Program in Molecular Medicine, University of Massachusetts Medical School Worcester, MA, USA
| | - Jeffrey A Bailey
- Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical SchoolWorcester, MA, USA; Division of Transfusion Medicine, Department of Medicine, University of Massachusetts Medical SchoolWorcester, MA, USA
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Monabati A, Vahedi A, Safaei A, Noori S, Mokhtari M, Vahedi L, Zamani M. Epstein-Barr Virus-Positive Diffuse Large B-Cell Lymphoma: Is It Different between Over and Under 50 Years of Age? Asian Pac J Cancer Prev 2017; 17:2285-9. [PMID: 27221931 DOI: 10.7314/apjcp.2016.17.4.2285] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Epstein-Barr virus (EBV) positive diffuse large B-cell lymphoma (DLBCL) of the elderly is an entity introduced in the latest WHO classification of lymphoid tumors and defined in patients older than 50 years without prior lymphoma or immunodeficiency. However, recently it has also been seen in patients under 50. There is thus debate as to whether these are separate entities. MATERIALS AND METHODS In this retrospective study, we analyzed de novo DLBCL admitted to our institute over a period of two years. Clinical data included age, sex, nodal and extranodal presentation. The results of an immunohistochemistry (IHC) panel were also reviewed. IHC findings were mainly used to sub-classify DLBCL as germinal center vs. non germinal center types. IHC for identification of LMP-1 (latent membrane protein) and in situ hybridization for detection of EBV- encoded RNA (EBER) was performed. EBV prevalence, clinical data and IHC findings were compared between patients under and over 50 years of age. RESULTS Out of 95 DLBCL, 11.6% were EBV positive (7.5% and 14.5% in the young and old groups). We did not find any significant differences in IHC subclasses and clinical data between EBV positive DLBCL (EBV+DLBCL) of young and old groups. CONCLUSIONS EBV+DLBCL are not exclusive to patients older than 50 years. With regard to clinical data as well as IHC subclasses, no differences were evident between EBV+DLBCL of young and old groups. Our suggestion is to eliminate any cut off age for EBV+DLBCL.
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Affiliation(s)
- Ahmad Monabati
- Department of Pathology and Hematology research center, Shiraz University of Medical Sciences, Shiraz, Iran E-mail :
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Liang Y, Ding L, Li X, Wang W, Zhang X. Oculomotor nerve palsy as a preceding symptom of adult sporadic Burkitt lymphoma: A case report and review of the literature. Oncol Lett 2017; 13:1315-1318. [PMID: 28454254 DOI: 10.3892/ol.2017.5583] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2015] [Accepted: 08/19/2016] [Indexed: 12/21/2022] Open
Abstract
Adult sporadic Burkitt lymphoma (BL) is a rare aggressive neoplasm and represents ~1-5% of all lymphomas diagnosed in adults. The disease exhibits an aggressive clinical manifestation, which frequently involves the central nervous system (CNS) in the early stages, and is usually accompanied by abnormalities in cerebrospinal fluid (CSF) examinations and/or neuroradiography. The current study describes the rare case of a 29-year-old man who presented with oculomotor nerve palsy without palpated masses, B symptoms, peripheral blood anomaly and abnormalities of the nervous system. The patient was initially misdiagnosed with abducens diplopia, but was subsequently confirmed to have BL with early CNS invasion. Epstein-Barr virus and human immunodeficiency virus infection were negative. Intensive systemic chemotherapy with hyperfractionated cyclophosphamide, vincristine, therarubicin and dexamethasone (hyper-CVAD, cyclophosphamide 600 mg/m2 on days 2-4; vincristine 1.4 mg/m2 on days 5 and 12, therarubicin 50 mg/m2 on day 5 and dexamethasone 40 mg on days 2-5 and 12-15), including intrathecal chemotherapy with methotrexate (5 mg), arabinocytidine (5 mg) and dexamethasone (5 mg), was determined as an appropriate treatment. Rituximab (375 mg/m2 on day 1) was administered alongside chemotherapy to increase treatment efficacy. The patient temporarily underwent complete remission, but subsequently relapsed as no suitable bone marrow donor was available. Adult sporadic BL with early CNS invasion, which traditional tests such as neuroradiography and CSF examination fail to identify, is uncommon. Therefore, appropriate diagnostic tests are critical for accurate diagnosis and must be performed immediately, particularly in patients that present with unusual image and laboratory manifestations.
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Affiliation(s)
- Yun Liang
- Department of Hematology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Luyin Ding
- Department of Hematology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Xian Li
- Department of Hematology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Weiqin Wang
- Department of Hematology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Xiaohong Zhang
- Department of Hematology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
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Dozzo M, Carobolante F, Donisi PM, Scattolin A, Maino E, Sancetta R, Viero P, Bassan R. Burkitt lymphoma in adolescents and young adults: management challenges. Adolesc Health Med Ther 2017; 8:11-29. [PMID: 28096698 PMCID: PMC5207020 DOI: 10.2147/ahmt.s94170] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
About one-half of all Burkitt lymphoma (BL) patients are younger than 40 years, and one-third belong to the adolescent and young adult (AYA) subset, defined by an age between 15 and 25-40 years, based on selection criteria used in different reports. BL is an aggressive B-cell neoplasm displaying highly characteristic clinico-diagnostic features, the biologic hallmark of which is a translocation involving immunoglobulin and c-MYC genes. It presents as sporadic, endemic, or epidemic disease. Endemicity is pathogenetically linked to an imbalance of the immune system which occurs in African children infected by malaria parasites and Epstein-Barr virus, while the epidemic form strictly follows the pattern of infection by HIV. BL shows propensity to extranodal involvement of abdominal organs, bone marrow, and central nervous system, and can cause severe metabolic and renal impairment. Nevertheless, BL is highly responsive to specifically designed short-intensive, rotational multiagent chemotherapy programs, empowered by the anti-CD20 monoclonal antibody rituximab. When carefully applied with appropriate supportive measures, these modern programs achieve a cure rate of approximately 90% in the average AYA patient, irrespective of clinical stage, which is the best result achievable in any aggressive lymphoid malignancy to date. The challenges ahead concern the following: optimization of management in underdeveloped countries, with reduction of diagnostic and referral-for-care intervals, and the applicability of currently curative regimens; the development of lower intensity but equally effective treatments for frail or immunocompromised patients at risk of death by complications; the identification of very high-risk patients through positron-emission tomography and minimal residual disease assays; and the assessment in these and the few refractory/relapsed ones of new monoclonals (ofatumumab, blinatumomab, inotuzumab ozogamicin) and new molecules targeting c-MYC and key proliferative steps of B-cell malignancies.
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Affiliation(s)
- Massimo Dozzo
- Complex Operative Unit of Hematology, Ospedale dell’Angelo
| | | | - Pietro Maria Donisi
- Simple Departmental Operative Unit of Anatomic Pathology, Ospedale Ss. Giovanni e Paolo, Venice, Italy
| | | | - Elena Maino
- Complex Operative Unit of Hematology, Ospedale dell’Angelo
| | | | - Piera Viero
- Complex Operative Unit of Hematology, Ospedale dell’Angelo
| | - Renato Bassan
- Complex Operative Unit of Hematology, Ospedale dell’Angelo
- Correspondence: Renato Bassan, Complex Operative Unit of Hematology, Ospedale dell’Angelo, Via Paccagnella 11, 30174 Mestre-Venice, Italy, Tel +39 41 965 7362, Fax +39 41 965 7361, Email
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