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Wang B, Reville PK, Abbas HA. Therapeutic hurdles in acute myeloid leukemia: Leukemic stem cells, inflammation and immune dysfunction. Curr Opin Pharmacol 2025; 82:102526. [PMID: 40318269 DOI: 10.1016/j.coph.2025.102526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 04/02/2025] [Accepted: 04/03/2025] [Indexed: 05/07/2025]
Abstract
Acute myeloid leukemia (AML) is an aggressive and highly heterogeneous hematological malignancy characterized by clonal expansion and differentiation arrest in myeloid progenitor cells. Despite advancements in chemotherapy, allogeneic hematopoietic stem cell transplantation, and post-remission maintenance therapies, the long-term survival remains unsatisfactory with high rates of relapse and refractory. These therapeutic challenges are mediated by multiple factors, including the complexity of the cellular hierarchies in AML, the interaction of leukemic stem cells (LSCs) with the bone marrow niche, inflammation, and immune evasion mechanisms. Further, the absence of specific surface markers that distinguish LSCs from normal hematopoietic stem cells, together with LSCs' functional heterogeneity, complicates targeted treatment approaches. Immune dysfunction, including T cell exhaustion and immune suppression within the bone marrow niche contributes to therapy resistance. In this brief review, we aim to explore current challenges in AML therapy, focusing on LSC-driven resistance, immune evasion, and the need for innovative therapeutic strategies.
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Affiliation(s)
- Bofei Wang
- Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Patrick K Reville
- Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hussein A Abbas
- Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genomic Medicine, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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2
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Haddadin L, Sun X. Stem Cells in Cancer: From Mechanisms to Therapeutic Strategies. Cells 2025; 14:538. [PMID: 40214491 PMCID: PMC11988674 DOI: 10.3390/cells14070538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2025] [Revised: 03/23/2025] [Accepted: 04/01/2025] [Indexed: 04/14/2025] Open
Abstract
Stem cells have emerged as a pivotal area of research in the field of oncology, offering new insights into the mechanisms of cancer initiation, progression, and resistance to therapy. This review provides a comprehensive overview of the role of stem cells in cancer, focusing on cancer stem cells (CSCs), their characteristics, and their implications for cancer therapy. We discuss the origin and identification of CSCs, their role in tumorigenesis, metastasis, and drug resistance, and the potential therapeutic strategies targeting CSCs. Additionally, we explore the use of normal stem cells in cancer therapy, focusing on their role in tissue regeneration and their use as delivery vehicles for anticancer agents. Finally, we highlight the challenges and future directions in stem cell research in cancer.
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Affiliation(s)
| | - Xueqin Sun
- Cancer Genome and Epigenetics Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
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Leck LYW, Abd El-Aziz YS, McKelvey KJ, Park KC, Sahni S, Lane DJR, Skoda J, Jansson PJ. Cancer stem cells: Masters of all traits. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167549. [PMID: 39454969 DOI: 10.1016/j.bbadis.2024.167549] [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: 02/05/2024] [Revised: 10/01/2024] [Accepted: 10/16/2024] [Indexed: 10/28/2024]
Abstract
Cancer is a heterogeneous disease, which contributes to its rapid progression and therapeutic failure. Besides interpatient tumor heterogeneity, tumors within a single patient can present with a heterogeneous mix of genetically and phenotypically distinct subclones. These unique subclones can significantly impact the traits of cancer. With the plasticity that intratumoral heterogeneity provides, cancers can easily adapt to changes in their microenvironment and therapeutic exposure. Indeed, tumor cells dynamically shift between a more differentiated, rapidly proliferating state with limited tumorigenic potential and a cancer stem cell (CSC)-like state that resembles undifferentiated cellular precursors and is associated with high tumorigenicity. In this context, CSCs are functionally located at the apex of the tumor hierarchy, contributing to the initiation, maintenance, and progression of tumors, as they also represent the subpopulation of tumor cells most resistant to conventional anti-cancer therapies. Although the CSC model is well established, it is constantly evolving and being reshaped by advancing knowledge on the roles of CSCs in different cancer types. Here, we review the current evidence of how CSCs play a pivotal role in providing the many traits of aggressive tumors while simultaneously evading immunosurveillance and anti-cancer therapy in several cancer types. We discuss the key traits and characteristics of CSCs to provide updated insights into CSC biology and highlight its implications for therapeutic development and improved treatment of aggressive cancers.
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Affiliation(s)
- Lionel Y W Leck
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Cancer Drug Resistance & Stem Cell Program, School of Medical Science, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
| | - Yomna S Abd El-Aziz
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Oral Pathology Department, Faculty of Dentistry, Tanta University, Tanta, Egypt
| | - Kelly J McKelvey
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia
| | - Kyung Chan Park
- Proteina Co., Ltd./Seoul National University, Seoul, South Korea
| | - Sumit Sahni
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia
| | - Darius J R Lane
- Melbourne Dementia Research Centre, The Florey Institute of Neuroscience & Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - Jan Skoda
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.
| | - Patric J Jansson
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Cancer Drug Resistance & Stem Cell Program, School of Medical Science, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia.
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Chen SY, Zhang YL, Li XR, Wang JR, Li KP, Wan S, Yang JW, Wang H, Cao JL, Wang CY, Fan XP, Fu SJ, Ding LY, Che TJ, Yang L. BIN1 inhibited tumor growth, metastasis and stemness by ALDH1/NOTCH pathway in bladder carcinoma. Hereditas 2025; 162:29. [PMID: 40016843 PMCID: PMC11866615 DOI: 10.1186/s41065-025-00384-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 02/01/2025] [Indexed: 03/01/2025] Open
Abstract
BACKGROUND Bladder cancer (BLCA) represents one of the most prevalent urological malignancies worldwide. Bridging integrator 1 (BIN1), a well-characterized tumor suppressor that interacts with and inhibits oncogenic Myc transcription factors, has demonstrated crucial roles in various cancer types. However, its specific functions and underlying molecular mechanisms in BLCA development and progression remain poorly understood. This study aims to elucidate the role of BIN1 in regulating BLCA cell proliferation, metastasis, and cancer stem cell properties. METHODS Using urinary proteomics analysis, we identified BIN1 as a significantly dysregulated protein in BLCA. The clinical significance of BIN1 was further validated through comprehensive analyses of public databases. BIN1 expression levels defined distinct molecular and immunological subtypes of BLCA. Through proteomic profiling of BIN1-overexpressing UMUC3 cells and corresponding controls, we identified ALDH1 as a key downstream effector in the BIN1-regulated ALDH1/NOTCH signaling axis. We employed multiple experimental approaches, including Western blot analysis, quantitative RT-PCR, immunofluorescence staining, wound healing assays, transwell migration assays, colony formation assays, tumor sphere formation assays, flow cytometry, CCK8 proliferation assays, and cell transfection experiments. RESULTS We observed significant downregulation of BIN1 in both BLCA tissues and cell lines compared to normal adjacent tissues and SV-HUC-1 cells, respectively. BIN1 overexpression inhibited cancer cell proliferation by promoting apoptosis and suppressed epithelial-mesenchymal transition (EMT), thereby reducing local invasion and distant metastasis. Additionally, BIN1 regulated cancer stem cell properties through modulation of ALDH1 expression, with NOTCH2 acting as a crucial downstream mediator of ALDH1 signaling. CONCLUSION Our findings demonstrate that BIN1 functions as a tumor suppressor in BLCA and suggest its potential utility as both a diagnostic biomarker and therapeutic target for BLCA treatment.
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Affiliation(s)
- Si-Yu Chen
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China
| | - Ya-Long Zhang
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China
| | - Xiao-Ran Li
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China
| | - Ji-Rong Wang
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China
| | - Kun-Peng Li
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China
| | - Shun Wan
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China
| | - Jian-Wei Yang
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China
| | - Hao Wang
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China
| | - Jin-Long Cao
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China
| | - Chen-Yang Wang
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China
| | - Xin-Peng Fan
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China
| | - Sheng-Jun Fu
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China
| | - Li-Yun Ding
- School of Physical Science and Technology, Lanzhou University, Lanzhou, China
| | - Tuan-Jie Che
- Baiyuan Company for Gene Technology, Lanzhou, China
| | - Li Yang
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China.
- Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China.
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Yao M, Yan W, Wang Y, Zhao Y, Xu X, Chen Y, Yu C, Li Y, Jiang H, Shen J, Cheng J, Xie C. IHCH9033, a novel class I HDAC inhibitor, synergizes with FLT3 inhibitor and rescues quizartinib resistance in FLT3-ITD AML via enhancing DNA damage response. Exp Hematol Oncol 2025; 14:15. [PMID: 39955584 PMCID: PMC11829435 DOI: 10.1186/s40164-025-00605-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 01/30/2025] [Indexed: 02/17/2025] Open
Abstract
BACKGROUND Despite initial success with FLT3 inhibitors (FLT3is), outcomes for FLT3-ITD acute myeloid leukemia (AML) patients remain unsatisfactory, underscoring the need for more effective treatment options. Epigenetic modifications, such as histone acetylation, contribute to AML's onset and persistence, advocating the potential for epigenetic therapies. However, the poor specificity of pan-histone deacetylase inhibitors (HDACis) leads to undesirable adverse effects, prompting the need for isoform-specific HDACis. This study aims to explore the antileukemic activities and mechanisms of IHCH9033, a novel class I HDACi, alone or combined with FLT3i in FLT3-ITD AML. METHODS The viability of AML cell lines and primary AML cells treated with HDACis alone or in combination with FLT3i was detected by MTT or CCK8 assay. Flow cytometry was utilized to examine cell apoptosis, cell cycle progression and ROS production. RNA sequencing analysis, RT-qPCR, western blotting, and co-immunoprecipitation assays were employed to elucidate the molecule mechanisms. The in vivo anti-leukemia efficacy was tested in xenografted mice models derived from FLT3-ITD cell lines and primary AML patients. RESULTS Here, we identified IHCH9033, a novel selective class I HDACi, which exhibited an increased antitumor effect in FLT3-ITD AML through effectively eliminating leukemia burden and overcoming resistance to FLT3i. Mechanically, IHCH9033 selectively inhibited DNA repair in FLT3-ITD AML cells, leading to the accumulation of DNA damage that eventually resulted in cell cycle arrest and apoptosis. Additionally, IHCH9033 induced HSP90 acetylation, FLT3 ubiquitination, and proteasomal degradation of FLT3, thereby inhibiting FLT3 downstream signaling. Notably, IHCH9033 maintained its potency in both FLT3i-resistant AML cell lines and primary-resistant patient samples, and exerted strong synergy with the FLT3i quizartinib, leading to tumor regression in FLT3-ITD/TKD AML xenografts. In patient-derived xenografts, the treatment with IHCH9033, both alone and in combination, led to nearly complete eradication of the AML burden, without significant adverse effects. CONCLUSIONS Our study shows that IHCH9033, a novel class I HDACi with a desirable pharmacological profile, is a promising drug candidate for FLT3-ITD AML, and suggests a strategy of combining class I HDACis and FLT3is in AML clinical trials to increase efficacy and overcome resistance, thus potentially providing a curative treatment option.
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Affiliation(s)
- Mingyue Yao
- Lingang Laboratory, 2380 Hechuan Road, Shanghai, 201101, China
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China
| | - Wenzhong Yan
- iHuman Institute, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China
| | - Yafang Wang
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China
| | - Yu Zhao
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Xiaowei Xu
- Department of Hematology, Shanghai Jiao Tong University School of Medicine Affiliated Shanghai General Hospital, Shanghai, 200025, China
| | - Yujun Chen
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Chengcheng Yu
- Lingang Laboratory, 2380 Hechuan Road, Shanghai, 201101, China
| | - Yingnian Li
- Lingang Laboratory, 2380 Hechuan Road, Shanghai, 201101, China
| | - Hualiang Jiang
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
- Drug Discovery and Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Jie Shen
- Department of Pharmacy, The SATCM Third Grade Laboratory of Traditional Chinese Medicine Preparations, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China.
| | - Jianjun Cheng
- iHuman Institute, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China.
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
| | - Chengying Xie
- Lingang Laboratory, 2380 Hechuan Road, Shanghai, 201101, China.
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China.
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
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Zhu C, Stiehl T. Modelling post-chemotherapy stem cell dynamics in the bone marrow niche of AML patients. Sci Rep 2024; 14:25060. [PMID: 39443599 PMCID: PMC11500015 DOI: 10.1038/s41598-024-75429-7] [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: 06/27/2024] [Accepted: 10/03/2024] [Indexed: 10/25/2024] Open
Abstract
Acute myeloid leukemia (AML) is a stem cell-driven malignancy of the blood forming (hematopoietic) system. Despite of high dose chemotherapy with toxic side effects, many patients eventually relapse. The "7+3 regimen", which consists of 7 days of cytarabine in combination with daunorubicin during the first 3 days, is a widely used therapy protocol. Since peripheral blood cells are easily accessible to longitudinal sampling, significant research efforts have been undertaken to characterize and reduce adverse effects on circulating blood cells. However, much less is known about the impact of the 7+3 regimen on human hematopoietic stem cells and their physiological micro-environments, the so-called stem cell niches. One reason for this is the technical inability to observe human stem cells in vivo and the discomfort related to bone marrow biopsies. To better understand the treatment effects on human stem cells, we consider a mechanistic mathematical model of the stem cell niche before, during and after chemotherapy. The model accounts for different maturation stages of leukemic and hematopoietic cells and considers key processes such as cell proliferation, self-renewal, differentiation and therapy-induced cell death. In the model, hematopoietic (HSCs) and leukemic stem cells (LSCs) compete for a joint niche and respond to both systemic and niche-derived signals. We relate the model to clinical trial data from literature which longitudinally quantifies the counts of hematopoietic stem like (CD34+CD38-ALDH+) cells at diagnosis and after therapy. The proposed model can capture the clinically observed interindividual heterogeneity and reproduce the non-monotonous dynamics of the hematopoietic stem like cells observed in relapsing patients. Our model allows to simulate different scenarios proposed in literature such as therapy-related impairment of the stem cell niche or niche-mediated resistance. Model simulations suggest that during the post-therapy phase a more than 10-fold increase of hematopoietic stem-like cell proliferation rates is required to recapitulate the measured cell dynamics in patients achieving complete remission. We fit the model to data of 7 individual patients and simulate variations of the treatment protocol. These simulations are in line with the clinical finding that G-CSF priming can improve the treatment outcome. Furthermore, our model suggests that a decline of HSC counts during remission might serve as an indication for salvage therapy in patients lacking MRD (minimal residual disease) markers.
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Affiliation(s)
- Chenxu Zhu
- Institute for Computational Biomedicine-Disease Modeling, RWTH Aachen University, Aachen, Germany
| | - Thomas Stiehl
- Institute for Computational Biomedicine-Disease Modeling, RWTH Aachen University, Aachen, Germany.
- Department of Science and Environment, Roskilde University, Roskilde, Denmark.
- Centre for Mathematical Modeling-Human Health and Disease, Roskilde University, Roskilde, Denmark.
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Kegyes D, Thiagarajan PS, Ghiaur G. MRD in Acute Leukemias: Lessons Learned from Acute Promyelocytic Leukemia. Cancers (Basel) 2024; 16:3208. [PMID: 39335179 PMCID: PMC11430625 DOI: 10.3390/cancers16183208] [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: 08/21/2024] [Revised: 09/12/2024] [Accepted: 09/18/2024] [Indexed: 09/30/2024] Open
Abstract
Introduction: Advances in molecular biology, polymerase chain reaction (PCR), and next-generation sequencing (NGS) have transformed the concept of minimal residual disease (MRD) from a philosophical idea into a measurable reality. Current Treatment Paradigms and Lessons Learned from APL: Acute promyelocytic leukemia (APL) leads the way in this transformation, initially using PCR to detect MRD in patients in remission, and more recently, aiming to eliminate it entirely with modern treatment strategies. Along the way, we have gained valuable insights that, when applied to other forms of acute leukemia, hold the potential to significantly improve the outcomes of these challenging diseases. Does the BM Microenvironment Play a Role in MRD?: In this review, we explore the current use of MRD in the management of acute leukemia and delve into the biological processes that contribute to MRD persistence, including its overlap with leukemia stem cells and the role of the bone marrow microenvironment.
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Affiliation(s)
- David Kegyes
- MedFuture Research Center for Advanced Medicine, Iuliu Hațieganu University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania
- The Sidney Kimmel Cancer Center, The Johns Hopkins University, Baltimore, MD 21205, USA
| | | | - Gabriel Ghiaur
- The Sidney Kimmel Cancer Center, The Johns Hopkins University, Baltimore, MD 21205, USA
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Liu Y, Zheng L, Li Y, Ma L, Zheng N, Liu X, Zhao Y, Yu L, Liu N, Liu S, Zhang K, Zhou J, Wei M, Yang C, Yang G. Neratinib impairs function of m6A recognition on AML1-ETO pre-mRNA and induces differentiation of t (8;21) AML cells by targeting HNRNPA3. Cancer Lett 2024; 594:216980. [PMID: 38797229 DOI: 10.1016/j.canlet.2024.216980] [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: 12/05/2023] [Revised: 05/07/2024] [Accepted: 05/19/2024] [Indexed: 05/29/2024]
Abstract
Acute myeloid leukemia (AML) is frequently linked to genetic abnormalities, with the t (8; 21) translocation, resulting in the production of a fusion oncoprotein AML1-ETO (AE), being a prevalent occurrence. This protein plays a pivotal role in t (8; 21) AML's onset, advancement, and recurrence, making it a therapeutic target. However, the development of drug molecules targeting AML1-ETO are markedly insufficient, especially used in clinical treatment. In this study, it was uncovered that Neratinib could significantly downregulate AML1-ETO protein level, subsequently promoting differentiation of t (8; 21) AML cells. Based on "differentiated active" probes, Neratinib was identified as a functional inhibitor against HNRNPA3 through covalent binding. The further studies demonstrated that HNRNPA3 function as a putative m6A reader responsible for recognizing and regulating the alternative splicing of AML-ETO pre-mRNA. These findings not only contribute to a novel insight to the mechanism governing post-transcriptional modification of AML1-ETO transcript, but also suggest that Neratinib would be promising therapeutic potential for t (8; 21) AML treatment.
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MESH Headings
- Humans
- Core Binding Factor Alpha 2 Subunit/genetics
- Core Binding Factor Alpha 2 Subunit/metabolism
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/drug therapy
- Leukemia, Myeloid, Acute/metabolism
- Leukemia, Myeloid, Acute/pathology
- Oncogene Proteins, Fusion/genetics
- Oncogene Proteins, Fusion/metabolism
- Quinolines/pharmacology
- Cell Differentiation/drug effects
- RUNX1 Translocation Partner 1 Protein/genetics
- RUNX1 Translocation Partner 1 Protein/metabolism
- RNA Precursors/metabolism
- RNA Precursors/genetics
- Heterogeneous-Nuclear Ribonucleoprotein Group A-B/metabolism
- Heterogeneous-Nuclear Ribonucleoprotein Group A-B/genetics
- Translocation, Genetic/drug effects
- Adenosine/analogs & derivatives
- Adenosine/metabolism
- Adenosine/pharmacology
- Alternative Splicing/drug effects
- Cell Line, Tumor
- Animals
- Mice
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Affiliation(s)
- Yulin Liu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, College of Life Sciences, Nankai University, Tianjin, 300071, PR China
| | - Liting Zheng
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, College of Life Sciences, Nankai University, Tianjin, 300071, PR China
| | - Ying Li
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, College of Life Sciences, Nankai University, Tianjin, 300071, PR China
| | - Lan Ma
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, College of Life Sciences, Nankai University, Tianjin, 300071, PR China
| | - Nan Zheng
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, College of Life Sciences, Nankai University, Tianjin, 300071, PR China
| | - Xinhua Liu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, College of Life Sciences, Nankai University, Tianjin, 300071, PR China
| | - Yanli Zhao
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, College of Life Sciences, Nankai University, Tianjin, 300071, PR China
| | - Li Yu
- Department of Hematology and Oncology, International Cancer Center, Shenzhen Key Laboratory of Precision Medicine for Hematological Malignancies, Shenzhen University General Hospital, Shenzhen University Clinical Medical Academy, Shenzhen University Health Science Center, Xueyuan AVE 1098, Nanshan District, Shenzhen, Guangdong, 518000, PR China
| | - Ning Liu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, College of Life Sciences, Nankai University, Tianjin, 300071, PR China.
| | - Shuangwei Liu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, College of Life Sciences, Nankai University, Tianjin, 300071, PR China.
| | - Kun Zhang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, College of Life Sciences, Nankai University, Tianjin, 300071, PR China.
| | - Jingfeng Zhou
- Department of Hematology and Oncology, International Cancer Center, Shenzhen Key Laboratory of Precision Medicine for Hematological Malignancies, Shenzhen University General Hospital, Shenzhen University Clinical Medical Academy, Shenzhen University Health Science Center, Xueyuan AVE 1098, Nanshan District, Shenzhen, Guangdong, 518000, PR China.
| | - Mingming Wei
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, College of Life Sciences, Nankai University, Tianjin, 300071, PR China.
| | - Cheng Yang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, College of Life Sciences, Nankai University, Tianjin, 300071, PR China.
| | - Guang Yang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, College of Life Sciences, Nankai University, Tianjin, 300071, PR China.
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9
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Chu X, Tian W, Ning J, Xiao G, Zhou Y, Wang Z, Zhai Z, Tanzhu G, Yang J, Zhou R. Cancer stem cells: advances in knowledge and implications for cancer therapy. Signal Transduct Target Ther 2024; 9:170. [PMID: 38965243 PMCID: PMC11224386 DOI: 10.1038/s41392-024-01851-y] [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: 10/02/2023] [Revised: 03/27/2024] [Accepted: 04/28/2024] [Indexed: 07/06/2024] Open
Abstract
Cancer stem cells (CSCs), a small subset of cells in tumors that are characterized by self-renewal and continuous proliferation, lead to tumorigenesis, metastasis, and maintain tumor heterogeneity. Cancer continues to be a significant global disease burden. In the past, surgery, radiotherapy, and chemotherapy were the main cancer treatments. The technology of cancer treatments continues to develop and advance, and the emergence of targeted therapy, and immunotherapy provides more options for patients to a certain extent. However, the limitations of efficacy and treatment resistance are still inevitable. Our review begins with a brief introduction of the historical discoveries, original hypotheses, and pathways that regulate CSCs, such as WNT/β-Catenin, hedgehog, Notch, NF-κB, JAK/STAT, TGF-β, PI3K/AKT, PPAR pathway, and their crosstalk. We focus on the role of CSCs in various therapeutic outcomes and resistance, including how the treatments affect the content of CSCs and the alteration of related molecules, CSCs-mediated therapeutic resistance, and the clinical value of targeting CSCs in patients with refractory, progressed or advanced tumors. In summary, CSCs affect therapeutic efficacy, and the treatment method of targeting CSCs is still difficult to determine. Clarifying regulatory mechanisms and targeting biomarkers of CSCs is currently the mainstream idea.
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Affiliation(s)
- Xianjing Chu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Wentao Tian
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Jiaoyang Ning
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Gang Xiao
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Yunqi Zhou
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Ziqi Wang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Zhuofan Zhai
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Guilong Tanzhu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
| | - Jie Yang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, China.
| | - Rongrong Zhou
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, China.
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10
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Nwosu GO, Ross DM, Powell JA, Pitson SM. Venetoclax therapy and emerging resistance mechanisms in acute myeloid leukaemia. Cell Death Dis 2024; 15:413. [PMID: 38866760 PMCID: PMC11169396 DOI: 10.1038/s41419-024-06810-7] [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: 03/21/2024] [Revised: 06/05/2024] [Accepted: 06/05/2024] [Indexed: 06/14/2024]
Abstract
Acute myeloid leukaemia (AML) is a highly aggressive and devastating malignancy of the bone marrow and blood. For decades, intensive chemotherapy has been the frontline treatment for AML but has yielded only poor patient outcomes as exemplified by a 5-year survival rate of < 30%, even in younger adults. As knowledge of the molecular underpinnings of AML has advanced, so too has the development new strategies with potential to improve the treatment of AML patients. To date the most promising of these targeted agents is the BH3-mimetic venetoclax which in combination with standard of care therapies, has manageable non-haematological toxicity and exhibits impressive efficacy. However, approximately 30% of AML patients fail to respond to venetoclax-based regimens and almost all treatment responders eventually relapse. Here, we review the emerging mechanisms of intrinsic and acquired venetoclax resistance in AML and highlight recent efforts to identify novel strategies to overcome resistance to venetoclax.
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Affiliation(s)
- Gus O Nwosu
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia
- Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia
| | - David M Ross
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia
- Adelaide Medical School, Faculty of Health Sciences, University of Adelaide, Adelaide, SA, Australia
- Department of Haematology, Royal Adelaide Hospital, Central Adelaide Local Health Network, Adelaide, SA, Australia
- Department of Haematology, Flinders University and Medical Centre, Adelaide, SA, Australia
| | - Jason A Powell
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.
- Adelaide Medical School, Faculty of Health Sciences, University of Adelaide, Adelaide, SA, Australia.
| | - Stuart M Pitson
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.
- Adelaide Medical School, Faculty of Health Sciences, University of Adelaide, Adelaide, SA, Australia.
- School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia.
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11
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Liu H, Wu K, Hu W, Chen X, Tang Y, Ma Y, Chen C, Xie Y, Yu L, Huang J, Shen S, Wang X. Immunophenotypic clustering in paediatric acute myeloid leukaemia. Br J Haematol 2024; 204:2275-2286. [PMID: 38639201 DOI: 10.1111/bjh.19471] [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: 01/25/2024] [Revised: 03/30/2024] [Accepted: 04/04/2024] [Indexed: 04/20/2024]
Abstract
Acute myeloid leukaemia (AML) is a highly heterogeneous disease, exhibiting diverse subtypes according to the characteristics of tumour cells. The immunophenotype is one of the aspects acquired routinely through flow cytometry in the diagnosis of AML. Here, we characterized the antigen expression in paediatric AML cases across both morphological and molecular genetic subgroups. We discovered a subgroup of patients with unfavourable prognosis that can be immunologically characterized, irrespective of morphological FAB results or genetic aberrations. Cox regression analysis unveiled key antigens influencing the prognosis of AML patients. In terms of underlying genotypes, we observed that the antigenic profiles and outcomes of one specific group, primarily composed of CBFA2T3::GLIS2 and FUS::ERG, were analogous to the reported RAM phenotype. Overall, our data highlight the significance of immunophenotype to tailor treatment for paediatric AML.
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Affiliation(s)
- Hui Liu
- Key Laboratory of Pediatric Hematology & Oncology of the Ministry of Health of China, Department of Hematology & Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Kefei Wu
- Key Laboratory of Pediatric Hematology & Oncology of the Ministry of Health of China, Department of Hematology & Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Wenting Hu
- Key Laboratory of Pediatric Hematology & Oncology of the Ministry of Health of China, Department of Hematology & Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaoxiao Chen
- Key Laboratory of Pediatric Hematology & Oncology of the Ministry of Health of China, Department of Hematology & Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yanjing Tang
- Key Laboratory of Pediatric Hematology & Oncology of the Ministry of Health of China, Department of Hematology & Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yani Ma
- Key Laboratory of Pediatric Hematology & Oncology of the Ministry of Health of China, Department of Hematology & Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Changcheng Chen
- Key Laboratory of Pediatric Hematology & Oncology of the Ministry of Health of China, Department of Hematology & Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yangyang Xie
- Key Laboratory of Pediatric Hematology & Oncology of the Ministry of Health of China, Department of Hematology & Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Lisha Yu
- Key Laboratory of Pediatric Hematology & Oncology of the Ministry of Health of China, Department of Hematology & Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jun Huang
- Key Laboratory of Pediatric Hematology & Oncology of the Ministry of Health of China, Department of Hematology & Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Shuhong Shen
- Key Laboratory of Pediatric Hematology & Oncology of the Ministry of Health of China, Department of Hematology & Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiang Wang
- Key Laboratory of Pediatric Hematology & Oncology of the Ministry of Health of China, Department of Hematology & Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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12
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Bo Y, Zhou J, Cai K, Wang Y, Feng Y, Li W, Jiang Y, Kuo SH, Roy J, Anorma C, Gardner SH, Luu LM, Lau GW, Bao Y, Chan J, Wang H, Cheng J. Leveraging intracellular ALDH1A1 activity for selective cancer stem-like cell labeling and targeted treatment via in vivo click reaction. Proc Natl Acad Sci U S A 2023; 120:e2302342120. [PMID: 37639589 PMCID: PMC10483628 DOI: 10.1073/pnas.2302342120] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 06/09/2023] [Indexed: 08/31/2023] Open
Abstract
Inhibition of overexpressed enzymes is among the most promising approaches for targeted cancer treatment. However, many cancer-expressed enzymes are "nonlethal," in that the inhibition of the enzymes' activity is insufficient to kill cancer cells. Conventional antibody-based therapeutics can mediate efficient treatment by targeting extracellular nonlethal targets but can hardly target intracellular enzymes. Herein, we report a cancer targeting and treatment strategy to utilize intracellular nonlethal enzymes through a combination of selective cancer stem-like cell (CSC) labeling and Click chemistry-mediated drug delivery. A de novo designed compound, AAMCHO [N-(3,4,6-triacetyl- N-azidoacetylmannosamine)-cis-2-ethyl-3-formylacrylamideglycoside], selectively labeled cancer CSCs in vitro and in vivo through enzymatic oxidation by intracellular aldehyde dehydrogenase 1A1. Notably, azide labeling is more efficient in identifying tumorigenic cell populations than endogenous markers such as CD44. A dibenzocyclooctyne (DBCO)-toxin conjugate, DBCO-MMAE (Monomethylauristatin E), could next target the labeled CSCs in vivo via bioorthogonal Click reaction to achieve excellent anticancer efficacy against a series of tumor models, including orthotopic xenograft, drug-resistant tumor, and lung metastasis with low toxicity. A 5/7 complete remission was observed after single-cycle treatment of an advanced triple-negative breast cancer xenograft (~500 mm3).
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Affiliation(s)
- Yang Bo
- Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL61801
| | - Jingyi Zhou
- Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL61801
| | - Kaimin Cai
- Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL61801
- Iria Pharma,Champaign, IL61820
| | - Ying Wang
- Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL61801
| | - Yujun Feng
- Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL61801
| | - Wenming Li
- Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL61801
| | - Yunjiang Jiang
- Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL61801
| | - Shanny Hsuan Kuo
- Department of Pathobiology at College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL61801
| | - Jarron Roy
- Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL61801
| | - Chelsea Anorma
- Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL61801
| | - Sarah H. Gardner
- Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL61801
| | | | - Gee W. Lau
- Department of Pathobiology at College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL61801
| | - Yan Bao
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong510120, China
| | - Jefferson Chan
- Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL61801
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL61801
| | - Hua Wang
- Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL61801
- Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL61801
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL61801
- Institute of Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL61801
- Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL61801
- School of Engineering, Westlake University, Hangzhou, Zhejiang Province310024, China
| | - Jianjun Cheng
- Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL61801
- Iria Pharma,Champaign, IL61820
- Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL61801
- Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL61801
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL61801
- Institute of Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL61801
- Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL61801
- School of Engineering, Westlake University, Hangzhou, Zhejiang Province310024, China
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13
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Bruserud Ø, Reikvam H. Casein Kinase 2 (CK2): A Possible Therapeutic Target in Acute Myeloid Leukemia. Cancers (Basel) 2023; 15:3711. [PMID: 37509370 PMCID: PMC10378128 DOI: 10.3390/cancers15143711] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Revised: 07/14/2023] [Accepted: 07/20/2023] [Indexed: 07/30/2023] Open
Abstract
The protein kinase CK2 (also known as casein kinase 2) is one of the main contributors to the human phosphoproteome. It is regarded as a possible therapeutic strategy in several malignant diseases, including acute myeloid leukemia (AML), which is an aggressive bone marrow malignancy. CK2 is an important regulator of intracellular signaling in AML cells, especially PI3K-Akt, Jak-Stat, NFκB, Wnt, and DNA repair signaling. High CK2 levels in AML cells at the first time of diagnosis are associated with decreased survival (i.e., increased risk of chemoresistant leukemia relapse) for patients receiving intensive and potentially curative antileukemic therapy. However, it is not known whether these high CK2 levels can be used as an independent prognostic biomarker because this has not been investigated in multivariate analyses. Several CK2 inhibitors have been developed, but CX-4945/silmitasertib is best characterized. This drug has antiproliferative and proapoptotic effects in primary human AML cells. The preliminary results from studies of silmitasertib in the treatment of other malignancies suggest that gastrointestinal and bone marrow toxicities are relatively common. However, clinical AML studies are not available. Taken together, the available experimental and clinical evidence suggests that the possible use of CK2 inhibition in the treatment of AML should be further investigated.
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Affiliation(s)
- Øystein Bruserud
- Institute for Clinical Science, Faculty of Medicine, University of Bergen, 5021 Bergen, Norway
- Section for Hematology, Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway
| | - Håkon Reikvam
- Institute for Clinical Science, Faculty of Medicine, University of Bergen, 5021 Bergen, Norway
- Section for Hematology, Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway
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14
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Gomez-Salazar MA, Wang Y, Thottappillil N, Hardy RW, Alexandre M, Höller F, Martin N, Gonzalez-Galofre ZN, Stefancova D, Medici D, James AW, Péault B. Aldehyde Dehydrogenase, a Marker of Normal and Malignant Stem Cells, Typifies Mesenchymal Progenitors in Perivascular Niches. Stem Cells Transl Med 2023; 12:474-484. [PMID: 37261440 PMCID: PMC10651226 DOI: 10.1093/stcltm/szad024] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 04/07/2023] [Indexed: 06/02/2023] Open
Abstract
Innate mesenchymal stem cells exhibiting multilineage differentiation and tissue (re)generative-or pathogenic-properties reside in perivascular niches. Subsets of these progenitors are committed to either osteo-, adipo-, or fibrogenesis, suggesting the existence of a developmental organization in blood vessel walls. We evaluated herein the activity of aldehyde dehydrogenase, a family of enzymes catalyzing the oxidation of aldehydes into carboxylic acids and a reported biomarker of normal and malignant stem cells, within human adipose tissue perivascular areas. A progression of ALDHLow to ALDHHigh CD34+ cells was identified in the tunica adventitia. Mesenchymal stem cell potential was confined to ALDHHigh cells, as assessed by proliferation and multilineage differentiation in vitro of cells sorted by flow cytometry with a fluorescent ALDH substrate. RNA sequencing confirmed and validated that ALDHHigh cells have a progenitor cell phenotype and provided evidence that the main isoform in this fraction is ALDH1A1, which was confirmed by immunohistochemistry. This demonstrates that ALDH activity, which marks hematopoietic progenitors and stem cells in diverse malignant tumors, also typifies native, blood vessel resident mesenchymal stem cells.
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Affiliation(s)
- Mario A Gomez-Salazar
- Center for Regenerative Medicine and Center for Cardiovascular Research, University of Edinburgh, Edinburgh, UK
- Department of Pathology, Johns Hopkins University, Baltimore, MB, USA
| | - Yiyun Wang
- Department of Pathology, Johns Hopkins University, Baltimore, MB, USA
| | | | - Reef W Hardy
- Orthopaedic Hospital Research Center and Broad Stem Cell Research Center, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Manon Alexandre
- Center for Regenerative Medicine and Center for Cardiovascular Research, University of Edinburgh, Edinburgh, UK
- Polytech Marseille, Aix Marseille University, Marseille, France
| | - Fabian Höller
- Center for Regenerative Medicine and Center for Cardiovascular Research, University of Edinburgh, Edinburgh, UK
| | - Niall Martin
- Center for Regenerative Medicine and Center for Cardiovascular Research, University of Edinburgh, Edinburgh, UK
| | - Zaniah N Gonzalez-Galofre
- Center for Regenerative Medicine and Center for Cardiovascular Research, University of Edinburgh, Edinburgh, UK
| | - Dorota Stefancova
- Center for Regenerative Medicine and Center for Cardiovascular Research, University of Edinburgh, Edinburgh, UK
| | - Daniele Medici
- Center for Regenerative Medicine and Center for Cardiovascular Research, University of Edinburgh, Edinburgh, UK
| | - Aaron W James
- Department of Pathology, Johns Hopkins University, Baltimore, MB, USA
| | - Bruno Péault
- Center for Regenerative Medicine and Center for Cardiovascular Research, University of Edinburgh, Edinburgh, UK
- Orthopaedic Hospital Research Center and Broad Stem Cell Research Center, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
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15
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Li SQ, Chen M, Huang XY, Wang H, Chang YJ. Challenges facing minimal residual disease testing for acute myeloid leukemia and promising strategies to overcome them. Expert Rev Hematol 2023; 16:981-990. [PMID: 37978882 DOI: 10.1080/17474086.2023.2285985] [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: 08/24/2023] [Accepted: 11/16/2023] [Indexed: 11/19/2023]
Abstract
INTRODUCTION Minimal residual disease (MRD) has been an important biomarker for relapse prediction and treatment choice in patients with acute myeloid leukemia (AML). False-positive or false-negative MRD results due to the low specificity and sensitivity of techniques such as multiparameter flow cytometry (MFC), real-time quantitative polymerase chain reaction, and next-generation sequencing, as well as the biological characteristics of residual leukemia cells, including antigen shift, clone involution, heterogeneous genome of the blast cells, and lack of specific targets, all restrict the clinical use of MRD. AREAS COVERED We summarized the challenges of the techniques for MRD detection, and their application in the clinical setting. We also discussed strategies to overcome these challenges, such as the MFC MRD method based on leukemia stem cells, single-cell DNA sequencing or single-cell RNA sequencing for the investigation of biological characteristics of residual leukemia cells, and the potential of omics techniques for MRD detection. We further noted out that prospective clinical trials are needed to answer clinical questions related to MRD in patients with AML. EXPERT OPINION MRD is an important biomarker for individual therapy of patients with AML. In the future, it is important to increase the specificity and sensitivity of the detection techniques.
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Affiliation(s)
- Si-Qi Li
- National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People's Hospital & Peking University Institute of Hematology, Beijing, Xicheng District, P.R.C
| | - Man Chen
- Department of Laboratory Medicine, Hebei Yanda Ludaopei Hospital, Langfang, Hebei, P.R.C
| | - Xi-Yi Huang
- Department of Experimental Medicine, School of Public Health, Xiamen University, Xiamen, P.R.C
| | - Hui Wang
- Department of Laboratory Medicine, Hebei Yanda Ludaopei Hospital, Langfang, Hebei, P.R.C
| | - Ying-Jun Chang
- National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People's Hospital & Peking University Institute of Hematology, Beijing, Xicheng District, P.R.C
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16
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Tan J, Zhong M, Hu Y, Pan G, Yao J, Tang Y, Duan H, Jiang Y, Shan W, Lin J, Liu Y, Huang J, Zheng H, Zhou Y, Fu G, Li Z, Xu B, Zha J. Ritanserin suppresses acute myeloid leukemia by inhibiting DGKα to downregulate phospholipase D and the Jak-Stat/MAPK pathway. Discov Oncol 2023; 14:118. [PMID: 37392305 DOI: 10.1007/s12672-023-00737-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Accepted: 06/25/2023] [Indexed: 07/03/2023] Open
Abstract
Refractory or relapsed (R/R) AML is the most challenging form of AML to treat. Due to frequent genetic mutations, therapy alternatives are limited. Here, we identified the role of ritanserin and its target DGKα in AML. Several AML cell lines and primary patient cells were treated with ritanserin and subjected to cell proliferation, apoptosis and gene analyses with CCK-8 assay, Annexin V/PI assay and Western blotting, respectively. We also evaluated the function of the ritanserin target diacylglycerol kinase alpha (DGKα) in AML by bioinformatics. In vitro experiments have revealed that ritanserin inhibits AML progression in a dose- and time-dependent manner, and it shows an anti-AML effect in xenograft mouse models. We further demonstrated that the expression of DGKα was elevated in AML and correlated with poor survival. Mechanistically, ritanserin negatively regulates SphK1 expression through PLD signaling, also inhibiting the Jak-Stat and MAPK signaling pathways via DGKα. These findings suggest that DGKα may be an available therapeutic target and provide effective preclinical evidence of ritanserin as a promising treatment for AML.
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Affiliation(s)
- Jinshui Tan
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, Fujian, People's Republic of China
- Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, No. 55, Shizhen Hai Road, Xiamen, 361003, Fujian, People's Republic of China
| | - Mengya Zhong
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, Fujian, People's Republic of China
- Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, No. 55, Shizhen Hai Road, Xiamen, 361003, Fujian, People's Republic of China
| | - Yanyan Hu
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Innovation Center for Cell Biology, Xiamen University, Xiamen, 361002, Fujian, China
| | - Guangchao Pan
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, Fujian, People's Republic of China
- Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, No. 55, Shizhen Hai Road, Xiamen, 361003, Fujian, People's Republic of China
| | - Jingwei Yao
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, Fujian, People's Republic of China
- Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, No. 55, Shizhen Hai Road, Xiamen, 361003, Fujian, People's Republic of China
| | - Yuanfang Tang
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, Fujian, People's Republic of China
- Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, No. 55, Shizhen Hai Road, Xiamen, 361003, Fujian, People's Republic of China
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Innovation Center for Cell Biology, Xiamen University, Xiamen, 361002, Fujian, China
| | - Hongpeng Duan
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, Fujian, People's Republic of China
- Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, No. 55, Shizhen Hai Road, Xiamen, 361003, Fujian, People's Republic of China
| | - Yuelong Jiang
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, Fujian, People's Republic of China
- Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, No. 55, Shizhen Hai Road, Xiamen, 361003, Fujian, People's Republic of China
| | - Weihang Shan
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, Fujian, People's Republic of China
- Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, No. 55, Shizhen Hai Road, Xiamen, 361003, Fujian, People's Republic of China
| | - Jiaqi Lin
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, Fujian, People's Republic of China
- Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, No. 55, Shizhen Hai Road, Xiamen, 361003, Fujian, People's Republic of China
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Innovation Center for Cell Biology, Xiamen University, Xiamen, 361002, Fujian, China
| | - Yating Liu
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, Fujian, People's Republic of China
- Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, No. 55, Shizhen Hai Road, Xiamen, 361003, Fujian, People's Republic of China
| | - Jiewen Huang
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, Fujian, People's Republic of China
- Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, No. 55, Shizhen Hai Road, Xiamen, 361003, Fujian, People's Republic of China
- School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361002, Fujian, China
| | - Huijian Zheng
- The School of Clinical Medicine, Fujian Medical University, Fuzhou, 350122, Fujian, China
| | - Yong Zhou
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, Fujian, People's Republic of China
- Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, No. 55, Shizhen Hai Road, Xiamen, 361003, Fujian, People's Republic of China
| | - Guo Fu
- State Key Laboratory of Cellular Stress Biology, School of Medicine, Innovation Center for Cell Biology, Xiamen University, Xiamen, 361002, Fujian, China
| | - Zhifeng Li
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, Fujian, People's Republic of China
- Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, No. 55, Shizhen Hai Road, Xiamen, 361003, Fujian, People's Republic of China
| | - Bing Xu
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, Fujian, People's Republic of China.
- Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, No. 55, Shizhen Hai Road, Xiamen, 361003, Fujian, People's Republic of China.
| | - Jie Zha
- Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, Fujian, People's Republic of China.
- Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, No. 55, Shizhen Hai Road, Xiamen, 361003, Fujian, People's Republic of China.
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17
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Liu Y, Wei Y, Wang X, Ma L, Li X, Sun Y, Wu Y, Zhang L, Wang J, Li M, Zhang K, Wei M, Yang G, Yang C. Discovery of novel and bioavailable histone deacetylases and cyclin-dependent kinases dual inhibitor to impair the stemness of leukemia cells. Eur J Med Chem 2023; 249:115140. [PMID: 36736154 DOI: 10.1016/j.ejmech.2023.115140] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 01/17/2023] [Accepted: 01/18/2023] [Indexed: 01/22/2023]
Abstract
Acute myeloid leukemia (AML) has been confirmed as one of the most lethal heterogeneous clonal diseases. In addition to being essential for the development and progression of leukemia, leukemic stem cells (LSCs), a subpopulation of leukemia cells with stem cell characteristics, are also primarily responsible for the development of leukemia relapse and drug resistance. Elimination of stemness and induction of AML cell differentiation would become a promising and effective therapeutic strategy. In the present study, a novel class of HDACs/CDKs dual inhibitors was prepared and optimized. An active compound 33a has been identified, which exhibited potent and selective inhibition of CDK9, CDK12, CDK13, HDAC1, HDAC2 and HDAC3 at low nanomolar concentrations and significantly induced differentiation of leukemic stem-like cells and inhibited AML proliferation. Furthermore, the lead compound has relatively adequate oral bioavailability, suggesting that it might be used as a novel strategy to reduce the burden of LSCs and improve the prognosis for AML.
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Affiliation(s)
- Yulin Liu
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, 300071, PR China
| | - Yujiao Wei
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, 300071, PR China
| | - Xuan Wang
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, 300071, PR China
| | - Lan Ma
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, 300071, PR China
| | - Xuechun Li
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, 300071, PR China
| | - Yue Sun
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, 300071, PR China
| | - Yanjie Wu
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, 300071, PR China
| | - Li Zhang
- Department of Hematology and Oncology, International Cancer Center, Shenzhen Key Laboratory of Precision Medicine for Hematological Malignancies, Shenzhen University General Hospital, Shenzhen University Clinical Medical Academy, Shenzhen, Guangdong, 518000, PR China
| | - Jiefu Wang
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, PR China.
| | - Ming Li
- Cangzhou Institutes for Food and Drug Control, Cangzhou, 061000, PR China.
| | - Kun Zhang
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, 300071, PR China.
| | - Mingming Wei
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, 300071, PR China.
| | - Guang Yang
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, 300071, PR China.
| | - Cheng Yang
- The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, 300071, PR China.
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18
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Chen H, Bai Y, Kobayashi M, Xiao S, Cai W, Barajas S, Chen S, Miao J, Meke FN, Vemula S, Ropa JP, Croop JM, Boswell HS, Wan J, Jia Y, Liu H, Li LS, Altman JK, Eklund EA, Ji P, Tong W, Band H, Huang DT, Platanias LC, Zhang ZY, Liu Y. PRL2 phosphatase enhances oncogenic FLT3 signaling via dephosphorylation of the E3 ubiquitin ligase CBL at tyrosine 371. Blood 2023; 141:244-259. [PMID: 36206490 PMCID: PMC9936309 DOI: 10.1182/blood.2022016580] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 09/06/2022] [Accepted: 09/24/2022] [Indexed: 02/05/2023] Open
Abstract
Acute myeloid leukemia (AML) is an aggressive blood cancer with poor prognosis. FMS-like tyrosine kinase receptor-3 (FLT3) is one of the major oncogenic receptor tyrosine kinases aberrantly activated in AML. Although protein tyrosine phosphatase PRL2 is highly expressed in some subtypes of AML compared with normal human hematopoietic stem and progenitor cells, the mechanisms by which PRL2 promotes leukemogenesis are largely unknown. We discovered that genetic and pharmacological inhibition of PRL2 significantly reduce the burden of FLT3-internal tandem duplications-driven leukemia and extend the survival of leukemic mice. Furthermore, we found that PRL2 enhances oncogenic FLT3 signaling in leukemia cells, promoting their proliferation and survival. Mechanistically, PRL2 dephosphorylates the E3 ubiquitin ligase CBL at tyrosine 371 and attenuates CBL-mediated ubiquitination and degradation of FLT3, leading to enhanced FLT3 signaling in leukemia cells. Thus, our study reveals that PRL2 enhances oncogenic FLT3 signaling in leukemia cells through dephosphorylation of CBL and will likely establish PRL2 as a novel druggable target for AML.
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Affiliation(s)
- Hongxia Chen
- Department of Hematology and Oncology, Chongqing University Three Gorges Hospital, Chongqing, China
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL
- School of Medicine, Chongqing University, Chongqing, China
| | - Yunpeng Bai
- Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, and Institute for Drug Discovery, Purdue University, West Lafayette, IN
| | - Michihiro Kobayashi
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN
| | - Shiyu Xiao
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL
| | - Wenjie Cai
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN
| | - Sergio Barajas
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN
| | - Sisi Chen
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN
| | - Jinmin Miao
- Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, and Institute for Drug Discovery, Purdue University, West Lafayette, IN
| | - Frederick Nguele Meke
- Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, and Institute for Drug Discovery, Purdue University, West Lafayette, IN
| | - Sasidhar Vemula
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN
| | - James P. Ropa
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN
| | - James M. Croop
- Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN
| | - H. Scott Boswell
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Jun Wan
- Department of Medical Genetics, Indiana University, Indianapolis, IN
| | - Yuzhi Jia
- Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL
| | - Huiping Liu
- Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL
- Robert H. Lurie Comprehensive Cancer Center, Chicago, IL
| | - Loretta S. Li
- Robert H. Lurie Comprehensive Cancer Center, Chicago, IL
- Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL
| | - Jessica K. Altman
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL
- Robert H. Lurie Comprehensive Cancer Center, Chicago, IL
| | - Elizabeth A. Eklund
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL
- Robert H. Lurie Comprehensive Cancer Center, Chicago, IL
- Department of Medicine, Jesse Brown VA Medical Center, Chicago, IL
| | - Peng Ji
- Robert H. Lurie Comprehensive Cancer Center, Chicago, IL
- Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL
| | - Wei Tong
- Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA
| | - Hamid Band
- Department of Genetics, University of Nebraska Medical Center, Omaha, NB
| | - Danny T. Huang
- Cancer Research UK Beatson Institute and Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Leonidas C. Platanias
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL
- Robert H. Lurie Comprehensive Cancer Center, Chicago, IL
- Department of Medicine, Jesse Brown VA Medical Center, Chicago, IL
| | - Zhong-Yin Zhang
- Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, and Institute for Drug Discovery, Purdue University, West Lafayette, IN
| | - Yan Liu
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL
- Robert H. Lurie Comprehensive Cancer Center, Chicago, IL
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19
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Raza S, Rajak S, Tewari A, Gupta P, Chattopadhyay N, Sinha RA, Chakravarti B. Multifaceted role of chemokines in solid tumors: From biology to therapy. Semin Cancer Biol 2022; 86:1105-1121. [PMID: 34979274 PMCID: PMC7613720 DOI: 10.1016/j.semcancer.2021.12.011] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/27/2021] [Accepted: 12/29/2021] [Indexed: 02/07/2023]
Abstract
Chemokines are small secretory chemotactic cytokines that control the directed migration of immune cells. Chemokines are involved in both anti-and pro-tumorigenic immune responses. Accumulating evidence suggests that the balance between these responses is influenced by several factors such as the stage of tumorigenesis, immune cell activation, recruitment of immune activating or immunosuppressive cells in the tumor microenvironment (TME), and chemokine receptor expression on effector and regulatory target cells. Cancer cells engage in a complex network with their TME components via several factors including growth factors, cytokines and chemokines that are critical for the growth of primary tumor and metastasis. However, chemokines show a multifaceted role in tumor progression including maintenance of stem-like properties, tumor cell proliferation/survival/senescence, angiogenesis, and metastasis. The heterogeneity of solid tumors in primary and metastatic cancers presents a challenge to the development of successful cancer therapy. Despite extensive research on how solid tumors escape immune cell-mediated anti-tumor response, finding an effective therapy for metastatic cancer still remains a challenge. This review discusses the multifarious roles of chemokines in solid tumors including various chemokine signaling pathways such as CXCL8-CXCR1/2, CXCL9, 10, 11-CXCR3, CXCR4-CXCL12, CCL(X)-CCR(X) in primary and metastatic cancers. We further discuss the novel therapeutic approaches that have been developed by major breakthroughs in chemokine research to treat cancer patients by the strategic blockade/activation of these signaling axes alone or in combination with immunotherapies.
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Affiliation(s)
- Sana Raza
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014, India
| | - Sangam Rajak
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014, India
| | - Archana Tewari
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014, India
| | - Pratima Gupta
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014, India
| | - Naibedya Chattopadhyay
- Division of Endocrinology and CSIR-Central Drug Research Institute, Sitapur Road, Lucknow, 226 031, India
| | - Rohit Anthony Sinha
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014, India
| | - Bandana Chakravarti
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014, India.
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20
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Shrestha S, Banstola A, Jeong JH, Seo JH, Yook S. Targeting Cancer Stem Cells: Therapeutic and diagnostic strategies by the virtue of nanoparticles. J Control Release 2022; 348:518-536. [PMID: 35709876 DOI: 10.1016/j.jconrel.2022.06.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 06/08/2022] [Accepted: 06/09/2022] [Indexed: 12/18/2022]
Abstract
Cancer stem cells (CSCs) are the subpopulation of cells present within a tumor with the properties of self-renewing, differentiating, and proliferating. Owing to the presence of ATP-binding cassette drug pumps and increased expression of anti-apoptotic proteins, the conventional chemotherapeutic agents have failed to eliminate CSCs resulting in relapse and resistance of cancer. Therefore, to obtain long-lasting clinical responses and avoid the recurrence of cancer, it is crucial to develop an efficient strategy targeting CSCs by either employing a differentiation therapy or specifically delivering drugs to CSCs. Several intracellular and extracellular cancer specific biomarkers are overexpressed by CSCs and are utilized as targets for the development of new approaches in the diagnosis and treatment of CSCs. Moreover, several nanostructured particles, alone or in combination with current treatment approaches, have been used to improve the detection, imaging, and targeting of CSCs, thus addressing the limitations of cancer therapies. Targeting CSC surface markers, stemness-related signaling pathways, and tumor microenvironmental signals has improved the detection and eradication of CSCs and, therefore, tumor diagnosis and treatment. This review summarizes a variety of promising nanoparticles targeting the surface biomarkers of CSCs for the detection and eradication of tumor-initiating stem cells, used in combination with other treatment regimens.
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Affiliation(s)
- Samjhana Shrestha
- College of Pharmacy, Keimyung University, 1095 Dalgubeol-daero, Dalseo-Gu, Daegu 42601, Republic of Korea
| | - Asmita Banstola
- College of Pharmacy, Keimyung University, 1095 Dalgubeol-daero, Dalseo-Gu, Daegu 42601, Republic of Korea; Wellman Center for Photomedicine, Massachusetts General Hospital, Department of Dermatology, Harvard Medical School, Boston, MA 02114, USA
| | - Jee-Heon Jeong
- Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Ji Hae Seo
- Department of Biochemistry, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea
| | - Simmyung Yook
- College of Pharmacy, Keimyung University, 1095 Dalgubeol-daero, Dalseo-Gu, Daegu 42601, Republic of Korea.
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21
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Functional genomic approaches in acute myeloid leukemia: Insights into disease models and the therapeutic potential of reprogramming. Cancer Lett 2022; 533:215579. [DOI: 10.1016/j.canlet.2022.215579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 01/17/2022] [Accepted: 01/29/2022] [Indexed: 11/19/2022]
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22
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Meriç N, Kocabaş F. The Historical Relationship Between Meis1 and Leukemia. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1387:127-144. [DOI: 10.1007/5584_2021_705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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23
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Touil Y, Latreche-Carton C, Bouazzati HE, Nugues AL, Jouy N, Thuru X, Laine W, Lepretre F, Figeac M, Tardivel M, Kluza J, Idziorek T, Quesnel B. p65/RelA NF-κB fragments generated by RIPK3 activity regulate tumorigenicity, cell metabolism, and stemness characteristics. J Cell Biochem 2021; 123:543-556. [PMID: 34927768 PMCID: PMC9299825 DOI: 10.1002/jcb.30198] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 11/17/2021] [Accepted: 12/10/2021] [Indexed: 12/16/2022]
Abstract
Receptor‐interacting protein kinase 3 (RIPK3) can induce necroptosis, apoptosis, or cell proliferation and is silenced in several hematological malignancies. We previously reported that RIPK3 activity independent of its kinase domain induces caspase‐mediated p65/RelA cleavage, resulting in N‐terminal 1‐361 and C‐terminal 362‐549 fragments. We show here that a noncleavable p65/RelA D361E mutant expressed in DA1‐3b leukemia cells decreases mouse survival times and that coexpression of p65/RelA fragments increases the tumorigenicity of B16F1 melanoma cells. This aggressiveness in vivo did not correlate with NF‐κB activity measured in vitro. The fragments and p65/RelA D361E mutant induced different expression profiles in DA1‐3b and B16F1 cells. Stemness markers were affected: p65/RelA D361E increased ALDH activity in DA1‐3b cells, and fragment expression increased melanoma sphere formation in B16/F1 cells. p65/RelA fragments and the D361E noncleavable mutant decreased oxidative or glycolytic cell metabolism, with differences observed between models. Thus, p65/RelA cleavage initiated by kinase‐independent RIPK3 activity in cancer cells is not neutral and induces pleiotropic effects in vitro and in vivo that may vary across tumor types.
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Affiliation(s)
- Yasmine Touil
- CANTHER, UMR 1277 Inserm - 9020 CNRS, University of Lille, Lille, France.,Institut pour la Recherche sur le Cancer de Lille, UMR 1277 Inserm - 9020 CNRS, Lille, France
| | - Céline Latreche-Carton
- CANTHER, UMR 1277 Inserm - 9020 CNRS, University of Lille, Lille, France.,Institut pour la Recherche sur le Cancer de Lille, UMR 1277 Inserm - 9020 CNRS, Lille, France
| | - Hassiba El Bouazzati
- CANTHER, UMR 1277 Inserm - 9020 CNRS, University of Lille, Lille, France.,Institut pour la Recherche sur le Cancer de Lille, UMR 1277 Inserm - 9020 CNRS, Lille, France
| | - Anne-Lucie Nugues
- CANTHER, UMR 1277 Inserm - 9020 CNRS, University of Lille, Lille, France.,Institut pour la Recherche sur le Cancer de Lille, UMR 1277 Inserm - 9020 CNRS, Lille, France
| | - Nathalie Jouy
- UMS 2014 CNRS/US 41 Inserm, University of Lille, Lille, France
| | - Xavier Thuru
- CANTHER, UMR 1277 Inserm - 9020 CNRS, University of Lille, Lille, France.,Institut pour la Recherche sur le Cancer de Lille, UMR 1277 Inserm - 9020 CNRS, Lille, France
| | - William Laine
- CANTHER, UMR 1277 Inserm - 9020 CNRS, University of Lille, Lille, France.,Institut pour la Recherche sur le Cancer de Lille, UMR 1277 Inserm - 9020 CNRS, Lille, France
| | | | - Martin Figeac
- UMS 2014 CNRS/US 41 Inserm, University of Lille, Lille, France
| | - Meryem Tardivel
- UMS 2014 CNRS/US 41 Inserm, University of Lille, Lille, France
| | - Jérôme Kluza
- CANTHER, UMR 1277 Inserm - 9020 CNRS, University of Lille, Lille, France.,Institut pour la Recherche sur le Cancer de Lille, UMR 1277 Inserm - 9020 CNRS, Lille, France
| | - Thierry Idziorek
- CANTHER, UMR 1277 Inserm - 9020 CNRS, University of Lille, Lille, France.,Institut pour la Recherche sur le Cancer de Lille, UMR 1277 Inserm - 9020 CNRS, Lille, France
| | - Bruno Quesnel
- CANTHER, UMR 1277 Inserm - 9020 CNRS, University of Lille, Lille, France.,Institut pour la Recherche sur le Cancer de Lille, UMR 1277 Inserm - 9020 CNRS, Lille, France.,Service des Maladies du Sang, CHU Lille, Lille, France
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24
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Webster JA, Yogarajah M, Zahurak M, Symons H, Dezern AE, Gojo I, Prince GT, Morrow J, Jones RJ, Smith BD, Showel M. A phase II study of azacitidine in combination with granulocyte-macrophage colony-stimulating factor as maintenance treatment, after allogeneic blood or marrow transplantation in patients with poor-risk acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Leuk Lymphoma 2021; 62:3181-3191. [PMID: 34284701 PMCID: PMC9195564 DOI: 10.1080/10428194.2021.1948029] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 05/14/2021] [Accepted: 06/17/2021] [Indexed: 10/20/2022]
Abstract
Relapse is the most common cause of treatment failure following allogeneic blood or marrow transplantation (alloBMT) for AML or MDS. Post-transplant maintenance therapies may prevent relapse. We conducted a phase II trial combining azacitidine (AZA) with GM-CSF in non-relapsed, post-transplant patients with AML or MDS. Patients received escalating doses of AZA to a maximum of 75 mg/m2 for 5 days per cycle for up to 12 cycles. GM-CSF was given on days 1-10 of each cycle. Eighteen patients were treated following non-myeloablative (17) and myeloablative (1) alloBMT for AML (61.1%), MDS (27.7%), or therapy-related myeloid neoplasm (11.1%). The majority of patients (72%) received their graft from an HLA-haploidentical donor. The treatment was well-tolerated with rare grade 3-4 hematologic toxicities. One patient suffered an exacerbation of GVHD. The 24-month relapse-free and overall survivals were 47 and 57%, respectively, with a median of 18.6 and 29 months.
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Affiliation(s)
- Jonathan A Webster
- Hematologic Malignancies and Bone Marrow Transplantation Program, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | - Marianna Zahurak
- Division of Biostatistics and Bioinformatics, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Heather Symons
- Hematologic Malignancies and Bone Marrow Transplantation Program, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Amy E Dezern
- Hematologic Malignancies and Bone Marrow Transplantation Program, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ivana Gojo
- Hematologic Malignancies and Bone Marrow Transplantation Program, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Gabrielle T Prince
- Hematologic Malignancies and Bone Marrow Transplantation Program, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jillian Morrow
- Hematologic Malignancies and Bone Marrow Transplantation Program, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Richard J Jones
- Hematologic Malignancies and Bone Marrow Transplantation Program, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - B Douglas Smith
- Hematologic Malignancies and Bone Marrow Transplantation Program, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Margaret Showel
- Hematologic Malignancies and Bone Marrow Transplantation Program, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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25
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Yi J, Wang L, Wang XY, Sun J, Yin XY, Hou JX, Chen J, Xie B, Wei HL. Suppression Of Aberrant Activation Of NF-κB Pathway In Drug-resistant Leukemia Stem Cells Contributes To Parthenolide-potentiated Reversal Of Drug Resistance In Leukemia. J Cancer 2021; 12:5519-5529. [PMID: 34405014 PMCID: PMC8364658 DOI: 10.7150/jca.52641] [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: 08/31/2020] [Accepted: 07/06/2021] [Indexed: 01/05/2023] Open
Abstract
Although many drugs that targeted the specific features of leukemia stem cells (LSCs) have substantial application in the clinical treatment of leukemia, the LSCs relapsed and caused drug-resistant leukemia. Therefore, it is necessary to identify the unique features of LSCs in relapsing and drug-resistant leukemia and also to explore the drugs that directed at these features. Our clinical data have indicated that relapsed patients with acute myeloid leukemia have more abundant proportion of LSCs with enhanced breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) expression when compared to the untreated patients. The results showed that compared with LSCs derived from sensitive K562 cells, LSCs from drug-resistant K562/ADM cells have much higher chemotherapeutic resistance, and so we termed these cells as “drug-resistant LSCs”. Subsequently, aberrant activation of NF-κB pathway in drug-resistant LSCs was further using gene chip analysis. Also, parthenolide (PTL), which is a specific NF-κB inhibitor, effectively eliminated drug-resistant LSCs and enhanced the sensitivity of K562/ADM cells to doxorubicin-induced apoptosis by down-regulating NF-κB pathway-mediated P-gp expression. These findings make the research area of LSCs more abundant and provide a potential therapeutic strategy for the treatment of refractory and relapsed leukemia.
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Affiliation(s)
- Juan Yi
- School of Basic Medical Sciences, Lanzhou University; Key Laboratory of Preclinical Study for New Drugs of Gansu Province, 99 Dong Gang West Road, Lanzhou, 730000 Gansu, China
| | - Li Wang
- School of Basic Medical Sciences, Lanzhou University; Key Laboratory of Preclinical Study for New Drugs of Gansu Province, 99 Dong Gang West Road, Lanzhou, 730000 Gansu, China
| | - Xiao-Yan Wang
- Gansu Provincial Maternity and Childcare Hospital, 143 North Street, Qi Li He district, Lanzhou, 730050, Gansu, China
| | - Jing Sun
- Lanzhou University Second Hospital, 80 Cui Ying Men, Lin Xia Road, Lanzhou, 730000 Gansu, China
| | - Xiao-Yang Yin
- School of Basic Medical Sciences, Lanzhou University; Key Laboratory of Preclinical Study for New Drugs of Gansu Province, 99 Dong Gang West Road, Lanzhou, 730000 Gansu, China
| | - Jin-Xia Hou
- School of Basic Medical Sciences, Lanzhou University; Key Laboratory of Preclinical Study for New Drugs of Gansu Province, 99 Dong Gang West Road, Lanzhou, 730000 Gansu, China
| | - Jing Chen
- School of Basic Medical Sciences, Lanzhou University; Key Laboratory of Preclinical Study for New Drugs of Gansu Province, 99 Dong Gang West Road, Lanzhou, 730000 Gansu, China
| | - Bei Xie
- School of Basic Medical Sciences, Lanzhou University; Key Laboratory of Preclinical Study for New Drugs of Gansu Province, 99 Dong Gang West Road, Lanzhou, 730000 Gansu, China
| | - Hu-Lai Wei
- School of Basic Medical Sciences, Lanzhou University; Key Laboratory of Preclinical Study for New Drugs of Gansu Province, 99 Dong Gang West Road, Lanzhou, 730000 Gansu, China.,State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P. R. China
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26
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Are polycythemia vera, essential thrombocytosis, and primary myelofibrosis 1, 2, or 3 diseases? Leukemia 2021; 35:1890-1893. [PMID: 33911177 DOI: 10.1038/s41375-021-01254-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 01/18/2021] [Accepted: 04/06/2021] [Indexed: 11/08/2022]
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27
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Yang Z, Wu XS, Wei Y, Polyanskaya SA, Iyer SV, Jung M, Lach FP, Adelman ER, Klingbeil O, Milazzo JP, Kramer M, Demerdash OE, Chang K, Goodwin S, Hodges E, McCombie WR, Figueroa ME, Smogorzewska A, Vakoc CR. Transcriptional Silencing of ALDH2 Confers a Dependency on Fanconi Anemia Proteins in Acute Myeloid Leukemia. Cancer Discov 2021; 11:2300-2315. [PMID: 33893150 DOI: 10.1158/2159-8290.cd-20-1542] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 03/23/2021] [Accepted: 04/21/2021] [Indexed: 12/31/2022]
Abstract
Hundreds of genes become aberrantly silenced in acute myeloid leukemia (AML), with most of these epigenetic changes being of unknown functional consequence. Here, we demonstrate how gene silencing can lead to an acquired dependency on the DNA repair machinery in AML. We make this observation by profiling the essentiality of the ubiquitination machinery in cancer cell lines using domain-focused CRISPR screening, which revealed Fanconi anemia (FA) proteins UBE2T and FANCL as unique dependencies in AML. We demonstrate that these dependencies are due to a synthetic lethal interaction between FA proteins and aldehyde dehydrogenase 2 (ALDH2), which function in parallel pathways to counteract the genotoxicity of endogenous aldehydes. We show DNA hypermethylation and silencing of ALDH2 occur in a recurrent manner in human AML, which is sufficient to confer FA pathway dependency. Our study suggests that targeting of the ubiquitination reaction catalyzed by FA proteins can eliminate ALDH2-deficient AML. SIGNIFICANCE: Aberrant gene silencing is an epigenetic hallmark of human cancer, but the functional consequences of this process are largely unknown. In this study, we show how an epigenetic alteration leads to an actionable dependency on a DNA repair pathway through the disabling of genetic redundancy.This article is highlighted in the In This Issue feature, p. 2113.
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Affiliation(s)
- Zhaolin Yang
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York
| | - Xiaoli S Wu
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.,Genetics Program, Stony Brook University, Stony Brook, New York
| | - Yiliang Wei
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York
| | | | - Shruti V Iyer
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.,Genetics Program, Stony Brook University, Stony Brook, New York
| | - Moonjung Jung
- Laboratory of Genome Maintenance, The Rockefeller University, New York, New York
| | - Francis P Lach
- Laboratory of Genome Maintenance, The Rockefeller University, New York, New York
| | - Emmalee R Adelman
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida
| | - Olaf Klingbeil
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York
| | | | - Melissa Kramer
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York
| | | | - Kenneth Chang
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York
| | - Sara Goodwin
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York
| | - Emily Hodges
- Department of Biochemistry and Vanderbilt Genetics Institute, Vanderbilt University School of Medicine, Nashville, Tennessee
| | | | - Maria E Figueroa
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida
| | - Agata Smogorzewska
- Laboratory of Genome Maintenance, The Rockefeller University, New York, New York
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28
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Aramini B, Masciale V, Grisendi G, Banchelli F, D'Amico R, Maiorana A, Morandi U, Dominici M, Haider KH. Cancer stem cells and macrophages: molecular connections and future perspectives against cancer. Oncotarget 2021; 12:230-250. [PMID: 33613850 PMCID: PMC7869576 DOI: 10.18632/oncotarget.27870] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 01/07/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer stem cells (CSCs) have been considered the key drivers of cancer initiation and progression due to their unlimited self-renewal capacity and their ability to induce tumor formation. Macrophages, particularly tumor-associated macrophages (TAMs), establish a tumor microenvironment to protect and induce CSCs development and dissemination. Many studies in the past decade have been performed to understand the molecular mediators of CSCs and TAMs, and several studies have elucidated the complex crosstalk that occurs between these two cell types. The aim of this review is to define the complex crosstalk between these two cell types and to highlight potential future anti-cancer strategies.
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Affiliation(s)
- Beatrice Aramini
- Division of Thoracic Surgery, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Valentina Masciale
- Division of Thoracic Surgery, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Giulia Grisendi
- Division of Oncology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Federico Banchelli
- Center of Statistic, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Roberto D'Amico
- Center of Statistic, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Antonino Maiorana
- Institute of Pathology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Uliano Morandi
- Division of Thoracic Surgery, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Massimo Dominici
- Division of Oncology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
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29
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Saeed BR, Manta L, Raffel S, Pyl PT, Buss EC, Wang W, Eckstein V, Jauch A, Trumpp A, Huber W, Ho AD, Lutz C. Analysis of nonleukemic cellular subcompartments reconstructs clonal evolution of acute myeloid leukemia and identifies therapy-resistant preleukemic clones. Int J Cancer 2021; 148:2825-2838. [PMID: 33411954 DOI: 10.1002/ijc.33461] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 07/16/2020] [Accepted: 08/27/2020] [Indexed: 12/19/2022]
Abstract
To acquire a better understanding of clonal evolution of acute myeloid leukemia (AML) and to identify the clone(s) responsible for disease recurrence, we have comparatively studied leukemia-specific mutations by whole-exome-sequencing (WES) of both the leukemia and the nonleukemia compartments derived from the bone marrow of AML patients. The T-lymphocytes, B-lymphocytes and the functionally normal hematopoietic stem cells (HSC), that is, CD34+ /CD38- /ALDH+ cells for AML with rare-ALDH+ blasts (<1.9% ALDH+ cells) were defined as the nonleukemia compartments. WES identified 62 point-mutations in the leukemia compartment derived from 12 AML-patients at the time of diagnosis and 73 mutations in 3 matched relapse cases. Most patients (8/12) showed 4 to 6 point-mutations per sample at diagnosis. Other than the mutations in the recurrently mutated genes such as DNMT3A, NRAS and KIT, we were able to identify novel point-mutations that have not yet been described in AML. Some leukemia-specific mutations and cytogenetic abnormalities including DNMT3A(R882H), EZH2(I146T) and inversion(16) were also detectable in the respective T-lymphocytes, B-lymphocytes and HSC in 5/12 patients, suggesting that preleukemia HSC might represent the source of leukemogenesis for these cases. The leukemic evolution was reconstructed for five cases with detectable preleukemia clones, which were tracked in follow-up and relapse samples. Four of the five patients with detectable preleukemic mutations developed relapse. The presence of leukemia-specific mutations in these nonleukemia compartments, especially after chemotherapy or after allogeneic stem cell transplantation, is highly relevant, as these could be responsible for relapse. This discovery may facilitate the identification of novel targets for long-term cure.
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Affiliation(s)
- Borhan R Saeed
- Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany
| | - Linda Manta
- Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany
| | - Simon Raffel
- Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Paul Theodor Pyl
- European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.,Division of Surgery, Oncology and Pathology, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, Lund, Sweden
| | - Eike C Buss
- Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany
| | - Wenwen Wang
- Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.,Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Volker Eckstein
- Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany
| | - Anna Jauch
- Institute of Human Genetics, Heidelberg University, Heidelberg, Germany
| | - Andreas Trumpp
- German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Wolfgang Huber
- European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Anthony D Ho
- Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany
| | - Christoph Lutz
- Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.,Praxis for Hematology and Oncology Koblenz, Koblenz, Germany
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30
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Stiehl T. Using mathematical models to improve risk-scoring in acute myeloid leukemia. CHAOS (WOODBURY, N.Y.) 2020; 30:123150. [PMID: 33380018 DOI: 10.1063/5.0023830] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 11/30/2020] [Indexed: 06/12/2023]
Abstract
Acute myeloid leukemia (AML) is an aggressive cancer of the blood forming (hematopoietic) system. Due to the high patient variability of disease dynamics, risk-scoring is an important part of its clinical management. AML is characterized by impaired blood cell formation and the accumulation of so-called leukemic blasts in the bone marrow of patients. Recently, it has been proposed to use counts of blood-producing (hematopoietic) stem cells (HSCs) as a biomarker for patient prognosis. In this work, we use a non-linear mathematical model to provide mechanistic evidence for the suitability of HSC counts as a prognostic marker. Using model analysis and computer simulations, we compare different risk-scores involving HSC quantification. We propose and validate a simple approach to improve risk prediction based on HSC and blast counts measured at the time of diagnosis.
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Affiliation(s)
- Thomas Stiehl
- Institute of Applied Mathematics, Heidelberg University, Im Neuenheimer Feld 205, 69120 Heidelberg, Germany
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31
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Yanagisawa B, Perkins B, Karantanos T, Levis M, Ghiaur G, Smith BD, Jones RJ. Expression of putative leukemia stem cell targets in genetically-defined acute myeloid leukemia subtypes. Leuk Res 2020; 99:106477. [PMID: 33220589 DOI: 10.1016/j.leukres.2020.106477] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 11/03/2020] [Accepted: 11/05/2020] [Indexed: 01/07/2023]
Abstract
Although most acute myeloid leukemia (AML) patients achieve complete remissions, the majority still eventually relapse and die of their disease. Rare primitive leukemia cells, so-called leukemia stem cells (LSCs), represent one potential type of resistant cell subpopulation responsible for this dissociation between response and cure. Several LSC targets have been described, but there is limited evidence about their relative utility or that targeting any can prevent relapse. LSCs not only appear to be biologically heterogeneous, but the classic immunocompromised mouse transplantation model also has serious shortcomings as an LSC assay. Out data suggest that the most immature cell phenotype that can be identified within a patient's leukemia may be clinically relevant and represent the de facto LSC. Moreover, although phenotypically heterogeneous, these putative LSCs show consistent phenotypes within individual genetically defined groups. Using this LSC definition, we studied several previously described putative LSC targets, CD25, CD26, CD47, CD96, CD123, and CLL-1, and all were expressed across heterogeneous LSC phenotypes. In addition, with the exception of CD47, there was at most low expression of these targets on normal hematopoietic stem cells (HSCs). CD123 and CLL-1 demonstrated the greatest expression differences between putative LSCs and normal HSCs. Importantly, CD123 monoclonal antibodies were cytotoxic in vitro to putative LSCs from all AML subtypes, while showing limited to no toxicity against normal HSCs and hematopoietic progenitors. Since minimal residual disease appears to be a more homogeneous population of cells responsible for relapse, targeting CD123 in this setting may be most effective.
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Affiliation(s)
- Breann Yanagisawa
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
| | - Brandy Perkins
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
| | | | - Mark Levis
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
| | - Gabriel Ghiaur
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
| | - B Douglas Smith
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
| | - Richard J Jones
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
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32
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Zabkiewicz J, Lazenby M, Edwards G, Bygrave CA, Omidvar N, Zhuang L, Knapper S, Guy C, Hills RK, Burnett AK, Alvares CL. Combination of a mitogen-activated protein kinase inhibitor with the tyrosine kinase inhibitor pacritinib combats cell adhesion-based residual disease and prevents re-expansion of FLT3-ITD acute myeloid leukaemia. Br J Haematol 2020; 191:231-242. [PMID: 32394450 DOI: 10.1111/bjh.16665] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 03/23/2020] [Indexed: 01/18/2023]
Abstract
Minimal residual disease (MRD) in acute myeloid leukaemia (AML) poses a major challenge due to drug insensitivity and high risk of relapse. Intensification of chemotherapy and stem cell transplantation are often pivoted on MRD status. Relapse rates are high even with the integration of first-generation FMS-like tyrosine kinase 3 (FLT3) inhibitors in pre- and post-transplant regimes and as maintenance in FLT3-mutated AML. Pre-clinical progress is hampered by the lack of suitable modelling of residual disease and post-therapy relapse. In the present study, we investigated the nature of pro-survival signalling in primary residual tyrosine kinase inhibitor (TKI)-treated AML cells adherent to stroma and further determined their drug sensitivity in order to inform rational future therapy combinations. Using a primary human leukaemia-human stroma model to mimic the cell-cell interactions occurring in patients, the ability of several TKIs in clinical use, to abrogate stroma-driven leukaemic signalling was determined, and a synergistic combination with a mitogen-activated protein kinase (MEK) inhibitor identified for potential therapeutic application in the MRD setting. The findings reveal a common mechanism of stroma-mediated resistance that may be independent of mutational status but can be targeted through rational drug design, to eradicate MRD and reduce treatment-related toxicity.
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MESH Headings
- Adolescent
- Adult
- Aged
- Antineoplastic Combined Chemotherapy Protocols/pharmacology
- Bridged-Ring Compounds/pharmacology
- Cell Adhesion/drug effects
- Child
- Child, Preschool
- Extracellular Signal-Regulated MAP Kinases
- Female
- Humans
- Infant
- Infant, Newborn
- Leukemia, Myeloid, Acute/drug therapy
- Leukemia, Myeloid, Acute/enzymology
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/pathology
- Male
- Middle Aged
- Models, Biological
- Neoplasm, Residual
- Protein Kinase Inhibitors/pharmacology
- Pyrimidines/pharmacology
- fms-Like Tyrosine Kinase 3/antagonists & inhibitors
- fms-Like Tyrosine Kinase 3/genetics
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Affiliation(s)
- Joanna Zabkiewicz
- Academic Department of Haematology, University of Cardiff, H, eath Park, Cardiff, UK
| | - Michelle Lazenby
- Academic Department of Haematology, University of Cardiff, H, eath Park, Cardiff, UK
| | - Gareth Edwards
- Academic Department of Haematology, University of Cardiff, H, eath Park, Cardiff, UK
| | - Ceri A Bygrave
- Academic Department of Haematology, University of Cardiff, H, eath Park, Cardiff, UK
| | - Nader Omidvar
- Academic Department of Haematology, University of Cardiff, H, eath Park, Cardiff, UK
| | - Lihui Zhuang
- Academic Department of Haematology, University of Cardiff, H, eath Park, Cardiff, UK
| | - Steve Knapper
- Academic Department of Haematology, University of Cardiff, H, eath Park, Cardiff, UK
| | - Carol Guy
- Academic Department of Haematology, University of Cardiff, H, eath Park, Cardiff, UK
| | - Robert K Hills
- Academic Department of Haematology, University of Cardiff, H, eath Park, Cardiff, UK
| | - Alan K Burnett
- Academic Department of Haematology, University of Cardiff, H, eath Park, Cardiff, UK
| | - Caroline L Alvares
- Academic Department of Haematology, University of Cardiff, H, eath Park, Cardiff, UK
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33
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Stiehl T, Wang W, Lutz C, Marciniak-Czochra A. Mathematical Modeling Provides Evidence for Niche Competition in Human AML and Serves as a Tool to Improve Risk Stratification. Cancer Res 2020; 80:3983-3992. [PMID: 32651258 DOI: 10.1158/0008-5472.can-20-0283] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 06/10/2020] [Accepted: 07/07/2020] [Indexed: 11/16/2022]
Abstract
Acute myeloid leukemia (AML) is a stem cell-driven malignant disease. There is evidence that leukemic stem cells (LSC) interact with stem cell niches and outcompete hematopoietic stem cells (HSC). The impact of this interaction on the clinical course of the disease remains poorly understood. We developed and validated a mathematical model of stem cell competition in the human HSC niche. Model simulations predicted how processes in the stem cell niche affect the speed of disease progression. Combining the mathematical model with data of individual patients, we quantified the selective pressure LSCs exert on HSCs and demonstrated the model's prognostic significance. A novel model-based risk-stratification approach allowed extraction of prognostic information from counts of healthy and malignant cells at the time of diagnosis. This model's feasibility was demonstrable based on a cohort of patients with ALDH-rare AML and shows that the model-based risk stratification is an independent predictor of disease-free and overall survival. This proof-of-concept study shows how model-based interpretation of patient data can improve prognostic scoring and contribute to personalized medicine. SIGNIFICANCE: Combining a novel mathematical model of the human hematopoietic stem cell niche with individual patient data enables quantification of properties of leukemic stem cells and improves risk stratification in acute myeloid leukemia.
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Affiliation(s)
- Thomas Stiehl
- Institute of Applied Mathematics and Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, Heidelberg, Germany.
| | - Wenwen Wang
- Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Christoph Lutz
- Department of Medicine V, Heidelberg University, Heidelberg, Germany
| | - Anna Marciniak-Czochra
- Institute of Applied Mathematics, Interdisciplinary Center for Scientific Computing (IWR) and Bioquant Center, Heidelberg University, Heidelberg, Germany
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34
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Morinishi L, Kochanowski K, Levine RL, Wu LF, Altschuler SJ. Loss of TET2 Affects Proliferation and Drug Sensitivity through Altered Dynamics of Cell-State Transitions. Cell Syst 2020; 11:86-94.e5. [PMID: 32619551 DOI: 10.1016/j.cels.2020.06.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 04/20/2020] [Accepted: 06/05/2020] [Indexed: 12/17/2022]
Abstract
A persistent puzzle in cancer biology is how mutations, which neither alter growth signaling pathways nor directly interfere with drug mechanism, can still recur and persist in tumors. One example is the mutation of the DNA demethylase tet methylcytosine dioxygenase 2 (TET2) in acute myeloid leukemias (AMLs) that frequently persists from diagnosis through remission and relapse, but whose fitness advantage in chemotherapy is unclear. Here, we use isogenic human AML cell lines to show that TET2 loss of function alters the dynamics of transitions between differentiated and stem-like states. A conceptual mathematical model and experimental validation suggest that these altered cell-state dynamics can benefit the cell population by slowing population decay during drug treatment and lowering the number of survivor cells needed to re-establish the initial population. These studies shed light on the functional and phenotypic effects of a TET2 mutation in AML and illustrate how a single gene mutation can alter a cells' phenotypic plasticity. A record of this paper's transparent peer review process is included in the Supplemental Information.
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Affiliation(s)
- Leanna Morinishi
- Bioinformatics Graduate Group, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Karl Kochanowski
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Ross L Levine
- Human Oncology and pathogenesis Program and Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Lani F Wu
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
| | - Steven J Altschuler
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
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35
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Tan Y, Wu Q, Zhou F. Targeting acute myeloid leukemia stem cells: Current therapies in development and potential strategies with new dimensions. Crit Rev Oncol Hematol 2020; 152:102993. [PMID: 32502928 DOI: 10.1016/j.critrevonc.2020.102993] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 05/15/2020] [Accepted: 05/15/2020] [Indexed: 12/12/2022] Open
Abstract
High relapse rate of acute myeloid leukemia (AML) is still a crucial problem despite considerable advances in anti-cancer therapies. One crucial cause of relapse is the existence of leukemia stem cells (LSCs) with self-renewal ability, which contribute to repeated treatment resistance and recurrence. Treatments targeting LSCs, especially in combination with existing chemotherapy regimens or hematopoietic stem cell transplantation might help achieve a higher complete remission rate and improve overall survival. Many novel agents of different therapeutic strategies that aim to modulate LSCs self-renewal, proliferation, apoptosis, and differentiation are under investigation. In this review, we summarize the latest advances of different therapies in development based on the biological characteristics of LSCs, with particular attention on natural products, synthetic compounds, antibody therapies, and adoptive cell therapies that promote the LSC eradication. We also explore the causes of AML recurrence and proposed potential strategies with new dimensions for targeting LSCs in the future.
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Affiliation(s)
- Yuxin Tan
- Department of Hematology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, 430071, People's Republic of China
| | - Qiuji Wu
- Department of Radiation and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, 430071, People's Republic of China
| | - Fuling Zhou
- Department of Hematology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, 430071, People's Republic of China.
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36
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Hanekamp D, Snel AN, Kelder A, Scholten WJ, Khan N, Metzner M, Irno-Consalvo M, Sugita M, de Jong A, Oude Alink S, Eidhof H, Wilhelm M, Feuring-Buske M, Slomp J, van der Velden VHJ, Sonneveld E, Guzman M, Roboz GJ, Buccisano F, Vyas P, Freeman S, Bachas C, Ossenkoppele GJ, Schuurhuis GJ, Cloos J. Applicability and reproducibility of acute myeloid leukaemia stem cell assessment in a multi-centre setting. Br J Haematol 2020; 190:891-900. [PMID: 32239670 PMCID: PMC7540683 DOI: 10.1111/bjh.16594] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 03/02/2020] [Indexed: 01/01/2023]
Abstract
Leukaemic stem cells (LSC) have been experimentally defined as the leukaemia‐propagating population and are thought to be the cellular reservoir of relapse in acute myeloid leukaemia (AML). Therefore, LSC measurements are warranted to facilitate accurate risk stratification. Previously, we published the composition of a one‐tube flow cytometric assay, characterised by the presence of 13 important membrane markers for LSC detection. Here we present the validation experiments of the assay in several large AML research centres, both in Europe and the United States. Variability within instruments and sample processing showed high correlations between different instruments (Rpearson > 0·91, P < 0·001). Multi‐centre testing introduced variation in reported LSC percentages but was found to be below the clinical relevant threshold. Clear gating protocols resulted in all laboratories being able to perform LSC assessment of the validation set. Participating centres were nearly unanimously able to distinguish LSChigh (>0·03% LSC) from LSClow (<0·03% LSC) despite inter‐laboratory variation in reported LSC percentages. This study proves that the LSC assay is highly reproducible. These results together with the high prognostic impact of LSC load at diagnosis in AML patients render the one‐tube LSC assessment a good marker for future risk classification.
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Affiliation(s)
- Diana Hanekamp
- Department of Hematology, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Alexander N Snel
- Department of Hematology, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Angèle Kelder
- Department of Hematology, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Willemijn J Scholten
- Department of Hematology, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Naeem Khan
- Institute of Immunology and Immunotherapy, Department of Clinical Immunology, University of Birmingham, Birmingham, United Kingdom
| | - Marlen Metzner
- Medical Research Council Molecular Hematology Unit, Oxford Centre for Hematology, Oxford BRC, University of Oxford and Oxford University Hospitals National Health Service Trust, Oxford, United Kingdom
| | - Maria Irno-Consalvo
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Mayumi Sugita
- Division of Hematology and Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Anja de Jong
- Dutch Childhood Oncology Group, Utrecht, the Netherlands
| | - Sjoerd Oude Alink
- Department of Immunology, Laboratory Medical Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Harrie Eidhof
- Department of Clinical Chemistry, Medisch Spectrum Twente/Medlon, Enschede, the Netherlands
| | - Miriam Wilhelm
- Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany
| | | | - Jennichjen Slomp
- Department of Clinical Chemistry, Medisch Spectrum Twente/Medlon, Enschede, the Netherlands
| | - Vincent H J van der Velden
- Department of Immunology, Laboratory Medical Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | | | - Monica Guzman
- Division of Hematology and Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Gail J Roboz
- Division of Hematology and Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Francesco Buccisano
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Paresh Vyas
- Medical Research Council Molecular Hematology Unit, Oxford Centre for Hematology, Oxford BRC, University of Oxford and Oxford University Hospitals National Health Service Trust, Oxford, United Kingdom
| | - Sylvie Freeman
- Institute of Immunology and Immunotherapy, Department of Clinical Immunology, University of Birmingham, Birmingham, United Kingdom
| | - Costa Bachas
- Department of Hematology, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Gert J Ossenkoppele
- Department of Hematology, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Gerrit J Schuurhuis
- Department of Hematology, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Jacqueline Cloos
- Department of Hematology, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, the Netherlands
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37
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Yang W, Xie J, Hou R, Chen X, Xu Z, Tan Y, Ren F, Zhang Y, Xu J, Chang J, Wang H. Disulfiram/cytarabine eradicates a subset of acute myeloid leukemia stem cells with high aldehyde dehydrogenase expression. Leuk Res 2020; 92:106351. [PMID: 32224355 DOI: 10.1016/j.leukres.2020.106351] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 03/15/2020] [Accepted: 03/16/2020] [Indexed: 01/07/2023]
Abstract
Most patients with acute myeloid leukemia (AML) achieve complete remission (CR) after induction chemotherapy, however, in some patients, the disease subsequently relapses and may lead to death. Leukemia stem cells (LSC) have been identified as the main cause for recurrence. Increased aldehyde dehydrogenase (ALDHhigh) activity in a variety of cancer stem cells prevents effective action of chemotherapeutic drugs. In this study, we found that approximately 50.7% of AML patients had ALDHhigh, and the presence of ALDHhigh stem cells was associated with poor cytogenetic prognosis. Lentiviral vector transduced ALDHhigh leukemia cell lines are insensitive to the conventional chemotherapy drug cytarabine, and inhibition of ALDH activity by disulfiram (DSF) can increase the sensitivity of ALDHhigh leukemia cells to cytarabine. Unlike traditional chemotherapy drugs, DSF is not toxic to healthy umbilical cord blood stem cells. An ALDHhigh leukemia cell xenograft model was established using immunodeficient mice to mimic the disease environment, and DSF and cytarabine were found to eliminate the ALDHhigh leukemia cells in transplanted mice while not affecting the healthy blood cells of mice. These findings suggest that DSF may have therapeutic potential by inhibiting ALDH activity and thereby increasing chemosensitivity.
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Affiliation(s)
- Wanfang Yang
- Institute of Hematology, The Second Hospital of Shanxi Medical University, Taiyuan, China; Shanxi University of Chinese Medicine, Jinzhong, China
| | - Juan Xie
- Institute of Hematology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Ruixia Hou
- Institute of Hematology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Xiuhua Chen
- Institute of Hematology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Zhifang Xu
- Institute of Hematology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Yanhong Tan
- Institute of Hematology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Fanggang Ren
- Institute of Hematology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Yaofang Zhang
- Institute of Hematology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Jing Xu
- Institute of Hematology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Jianmei Chang
- Institute of Hematology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Hongwei Wang
- Institute of Hematology, The Second Hospital of Shanxi Medical University, Taiyuan, China.
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38
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Patel SA, Gerber JM. A User's Guide to Novel Therapies for Acute Myeloid Leukemia. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2020; 20:277-288. [PMID: 32113891 DOI: 10.1016/j.clml.2020.01.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Revised: 01/20/2020] [Accepted: 01/21/2020] [Indexed: 01/01/2023]
Abstract
Few diseases have been marked by a 40-year period of stagnation with regard to therapeutic advances and United States Food and Drug Administration (FDA) approvals, as has been the case for acute myeloid leukemia (AML). Cytarabine and anthracyclines were introduced for the treatment of AML in the 1970s, and in the ensuing 4 decades, the pharmacologic pipeline has experienced a standstill. The absence of FDA approvals in AML is not a reflection of the lack of understanding of the disease biology. The field has seen major advances from the standpoint of stem cell biology and clonal evolution, and the field has also seen some therapeutic advances, but these therapeutic advances have arisen from optimization of the same traditional cytotoxic chemotherapeutics rather than the development of novel therapies. The year 2017 marked a turning point with regard to FDA approvals. This review summarizes the salient clinical trials that led to the approval of 8 novel agents in AML in the past 2 years. For these agents, the clinical activity is often defined by specific molecular aberrations or metabolic features of AML cells. We also emphasize the principles of management of AML in the current era of genomic medicine, with a focus on considerations for targeting mutation-specific vulnerabilities in select patients. This review also highlights unique challenges to the use of novel agents in 2020, including considerations of curative potential with regards to bridging to allogeneic stem cell transplant, tolerability, financial toxicities, and microenvironmental hurdles. Finally, we discuss prospects on future immunotherapeutic investigational agents in the pharmacologic pipeline.
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Affiliation(s)
- Shyam A Patel
- Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Medical School, UMass Memorial Medical Center, Worcester, MA
| | - Jonathan M Gerber
- Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Medical School, UMass Memorial Medical Center, Worcester, MA.
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Development of an anti-CD45RA-quantum dots conjugated scFv to detect leukemic cancer stem cells. Mol Biol Rep 2019; 47:225-234. [DOI: 10.1007/s11033-019-05122-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2019] [Accepted: 10/09/2019] [Indexed: 11/26/2022]
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40
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Vaisitti T, Arruga F, Guerra G, Deaglio S. Ectonucleotidases in Blood Malignancies: A Tale of Surface Markers and Therapeutic Targets. Front Immunol 2019; 10:2301. [PMID: 31636635 PMCID: PMC6788384 DOI: 10.3389/fimmu.2019.02301] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Accepted: 09/11/2019] [Indexed: 12/11/2022] Open
Abstract
Leukemia develops as the result of intrinsic features of the transformed cell, such as gene mutations and derived oncogenic signaling, and extrinsic factors, such as a tumor-friendly, immunosuppressed microenvironment, predominantly in the lymph nodes and the bone marrow. There, high extracellular levels of nucleotides, mainly NAD+ and ATP, are catabolized by different ectonucleotidases, which can be divided in two families according to substrate specificity: on one side those that metabolize NAD+, including CD38, CD157, and CD203a; on the other, those that convert ATP, namely CD39 (and other ENTPDases) and CD73. They generate products that modulate intracellular calcium levels and that activate purinergic receptors. They can also converge on adenosine generation with profound effects, both on leukemic cells, enhancing chemoresistance and homing, and on non-malignant immune cells, polarizing them toward tolerance. This review will first provide an overview of ectonucleotidases expression within the immune system, in physiological and pathological conditions. We will then focus on different hematological malignancies, discussing their role as disease markers and possibly pathogenic agents. Lastly, we will describe current efforts aimed at therapeutic targeting of this family of enzymes.
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Affiliation(s)
- Tiziana Vaisitti
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Francesca Arruga
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Giulia Guerra
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Silvia Deaglio
- Department of Medical Sciences, University of Turin, Turin, Italy
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41
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Brennan L, Narendran A. Cancer Stem Cells in the Development of Novel Therapeutics for Refractory Pediatric Leukemia. Stem Cells Dev 2019; 28:1277-1287. [PMID: 31364487 DOI: 10.1089/scd.2019.0035] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Although treatment strategies for pediatric leukemia have improved overall survival rates in the recent past, relapse rates in certain subgroups such as infant leukemia remain unacceptably high. Despite undergoing extensive chemotherapy designed to target the rapidly proliferating leukemia cells, many of these children experience relapse. In refractory leukemia, the existence of cell populations with stemness characteristics, termed leukemia stem cells (LSCs), which remain quiescent and subsequently replenish the blast population, has been described. A significant body of evidence exists, derived largely from xenograft models of adult acute myeloid leukemia, to support the idea that LSCs may play a fundamental role in refractory disease. In addition, clinical studies have also linked LSCs with increased minimal residual disease, higher relapse rate, and decreased survival rates in these patients. Recently, a number of reports have addressed effective ways to utilize new-generation genomic sequencing and transcriptomic analyses to identify targeted therapeutic agents aimed at LSCs, while sparing normal hematopoietic stem cells. These data underscore the value of timely translation of knowledge from adult studies to the unique molecular and physiological characteristics seen in pediatric leukemia. We aim to summarize this article in the rapidly expanding field of stem cell biology in hematopoietic malignancies, focusing particularly on relevant preclinical models and novel targeted therapeutics, and their applicability to childhood leukemia.
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Affiliation(s)
| | - Aru Narendran
- Division of Pediatric Hematology, Oncology and Transplant, POETIC Laboratory for Novel Therapeutics Discovery in Pediatric Oncology, Alberta Children's Hospital, Calgary, Canada
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42
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Schuurhuis GJ, Ossenkoppele GJ, Kelder A, Cloos J. Measurable residual disease in acute myeloid leukemia using flow cytometry: approaches for harmonization/standardization. Expert Rev Hematol 2019; 11:921-935. [PMID: 30466339 DOI: 10.1080/17474086.2018.1549479] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Introduction: Measurable residual disease (MRD) in acute myeloid leukemia (AML) is a rapidly evolving area with many institutes embarking on it, both in academic and pharmaceutical settings. However, there is a multitude of approaches to design, perform, and report flow cytometric MRD. Together with the long-term experience needed, this makes flow cytometric MRD in AML nonstandardized and time-consuming. Areas covered: This paper briefly summarizes critical issues, like sample preparation and transport, markers and fluorochromes of choice, but in particular focuses on the main issues, which includes specificity and sensitivity, hereby providing a new model that may circumvent the main disadvantages of the present approaches. New approaches that may add to the value of flow cytometric MRD includes assessment of leukemia stem cells, MRD in peripheral blood, and approaches to use multidimensional image analysis. Expert commentary: MRD in AML requires standardization/harmonization on many aspects, for which the present paper offers possible guidelines.
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Affiliation(s)
- Gerrit J Schuurhuis
- a Department of Hematology , VU University Medical Center , Amsterdam , Netherlands
| | - Gert J Ossenkoppele
- a Department of Hematology , VU University Medical Center , Amsterdam , Netherlands
| | - Angèle Kelder
- a Department of Hematology , VU University Medical Center , Amsterdam , Netherlands
| | - Jacqueline Cloos
- a Department of Hematology , VU University Medical Center , Amsterdam , Netherlands
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43
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Yang L, Chen WM, Dao FT, Zhang YH, Wang YZ, Chang Y, Liu YR, Jiang Q, Zhang XH, Liu KY, Huang XJ, Qin YZ. High aldehyde dehydrogenase activity at diagnosis predicts relapse in patients with t(8;21) acute myeloid leukemia. Cancer Med 2019; 8:5459-5467. [PMID: 31364309 PMCID: PMC6745853 DOI: 10.1002/cam4.2422] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 06/19/2019] [Accepted: 07/02/2019] [Indexed: 12/26/2022] Open
Abstract
Acute myeloid leukemia (AML) with t(8;21) is a heterogeneous disease. Although the detection of minimal residual disease (MRD), which is indicated by RUNX1‐RUNX1T1 transcript levels, plays a key role in directing treatment, risk stratification needs to be improved, and other markers need to be assessed. A total of 66 t(8;21) AML patients were tested for aldehyde dehydrogenase (ALDH) activity by flow cytometry at diagnosis, and 52 patients were followed up for a median of 20 (1‐34) months. The median percentage of CD34+ALDH+, CD34+CD38‐ALDH+, and CD34+CD38+ALDH+ cells among nucleated cells were 0.028%, 0.012%, and 0.0070%, respectively. The CD34+ALDH+‐H, CD34+CD38‐ALDH+‐H, and CD34+CD38+ALDH+‐H statuses (the percentage of cells that were higher than the individual cutoffs) were all significantly associated with a lower 2‐year relapse‐free survival (RFS) rate in both the whole cohort and adult patients (P = .015, .016, and .049; P = .014, .018, and .032). Patients with < 3‐log reduction in the RUNX1‐RUNX1T1 transcript level after the second consolidation therapy (defined as MRD‐H) had a significantly lower 2‐year RFS rate than patients with ≥ 3‐log reduction (MRD‐L) (P = .017). The CD34+ALDH+ status at diagnosis was then combined with the MRD status. CD34+ALDH+‐L/MRD‐H patients had similar 2‐year RFS rates to both CD34+ALDH+‐L/MRD‐L and CD34+ALDH+‐H/MRD‐L patients (P = .50 and 1.0); and CD34+ALDH+‐H/MRD‐H patients had significantly lower 2‐year RFS rate compared with CD34+ALDH+‐L and/or MRD‐L patients (P < .0001). Multivariate analysis showed that CD34+ALDH+‐H/MRD‐H was an independent adverse prognostic factor for relapse. In conclusion, ALDH status at diagnosis may improve MRD‐based risk stratification in t(8;21) AML, and concurrent high levels of CD34+ALDH+ at diagnosis and MRD predict relapse.
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Affiliation(s)
- Lu Yang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
| | - Wen-Min Chen
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
| | - Feng-Ting Dao
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
| | - Yan-Huan Zhang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
| | - Ya-Zhe Wang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
| | - Yan Chang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
| | - Yan-Rong Liu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
| | - Qian Jiang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
| | - Xiao-Hui Zhang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
| | - Kai-Yan Liu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
| | - Xiao-Jun Huang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
| | - Ya-Zhen Qin
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
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44
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Zhang Y, Xu C. G allele of rs7853346 polymorphism in PTENP1 enhances the proliferation of multiple myeloma cancer stem cells by promoting the expression of PTENP1 and its downstream signaling molecules. J Cell Biochem 2019; 120:19738-19748. [PMID: 31338886 DOI: 10.1002/jcb.29280] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2018] [Accepted: 03/22/2019] [Indexed: 12/14/2022]
Affiliation(s)
- Yehua Zhang
- Department of Hematology, Xingtai People's Hospital, Xingtai, Hebei, China
| | - Changqing Xu
- Emergency Department, Xingtai Third Hospital, Xingtai, Hebei, China
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45
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Aqaqe N, Yassin M, Yassin AA, Ershaid N, Katz-Even C, Zipin-Roitman A, Kugler E, Lechman ER, Gan OI, Mitchell A, Dick JE, Izraeli S, Milyavsky M. An ERG Enhancer-Based Reporter Identifies Leukemia Cells with Elevated Leukemogenic Potential Driven by ERG-USP9X Feed-Forward Regulation. Cancer Res 2019; 79:3862-3876. [PMID: 31175119 DOI: 10.1158/0008-5472.can-18-3215] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 03/21/2019] [Accepted: 06/04/2019] [Indexed: 11/16/2022]
Abstract
Acute leukemia is a rapidly progressing blood cancer with low survival rates. Unfavorable prognosis is attributed to insufficiently characterized subpopulations of leukemia stem cells (LSC) that drive chemoresistance and leukemia relapse. Here we utilized a genetic reporter that assesses stemness to enrich and functionally characterize LSCs. We observed heterogeneous activity of the ERG+85 enhancer-based fluorescent reporter in human leukemias. Cells with high reporter activity (tagBFPHigh) exhibited elevated expression of stemness and chemoresistance genes and demonstrated increased clonogenicity and resistance to chemo- and radiotherapy as compared with their tagBFPNeg counterparts. The tagBFPHigh fraction was capable of regenerating the original cellular heterogeneity and demonstrated increased invasive ability. Moreover, the tagBFPHigh fraction was enriched for leukemia-initiating cells in a xenograft assay. We identified the ubiquitin hydrolase USP9X as a novel ERG transcriptional target that sustains ERG+85-positive cells by controlling ERG ubiquitination. Therapeutic targeting of USP9X led to preferential inhibition of the ERG-dependent leukemias. Collectively, these results characterize human leukemia cell functional heterogeneity and suggest that targeting ERG via USP9X inhibition may be a potential treatment strategy in patients with leukemia. SIGNIFICANCE: This study couples a novel experimental tool with state-of-the-art approaches to delineate molecular mechanisms underlying stem cell-related characteristics in leukemia cells.
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Affiliation(s)
- Nasma Aqaqe
- Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Muhammad Yassin
- Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Abed Alkader Yassin
- Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Nour Ershaid
- Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Chen Katz-Even
- Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Adi Zipin-Roitman
- Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Eitan Kugler
- Department of Pediatric Hemato-Oncology, Schneider Children Medical Center Petah-Tikva, Israel.,The Gene Development and Environment Pediatric Research Institute, Pediatric Hemato-Oncology, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.,Department of Molecular Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Eric R Lechman
- Princess Margaret Cancer Centre, University Health Network and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - Olga I Gan
- Princess Margaret Cancer Centre, University Health Network and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - Amanda Mitchell
- Princess Margaret Cancer Centre, University Health Network and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - John E Dick
- Princess Margaret Cancer Centre, University Health Network and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - Shai Izraeli
- Department of Pediatric Hemato-Oncology, Schneider Children Medical Center Petah-Tikva, Israel.,The Gene Development and Environment Pediatric Research Institute, Pediatric Hemato-Oncology, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.,Department of Molecular Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Michael Milyavsky
- Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
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46
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Acute Myeloid Leukemia Stem Cell Heterogeneity and Its Clinical Relevance. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1139:153-169. [DOI: 10.1007/978-3-030-14366-4_9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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47
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Annageldiyev C, Gowda K, Patel T, Bhattacharya P, Tan SF, Iyer S, Desai D, Dovat S, Feith DJ, Loughran TP, Amin S, Claxton D, Sharma A. The novel Isatin analog KS99 targets stemness markers in acute myeloid leukemia. Haematologica 2019; 105:687-696. [PMID: 31123028 PMCID: PMC7049373 DOI: 10.3324/haematol.2018.212886] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2018] [Accepted: 05/22/2019] [Indexed: 01/01/2023] Open
Abstract
Leukemic stem cells are multipotent, self-renewing, highly proliferative cells that can withstand drug treatments. Although currently available treatments potentially destroy blast cells, they fail to eradicate leukemic progenitor cells completely. Aldehyde dehydrogenase and STAT3 are frequently up-regulated in pre-leukemic stem cells as well as in acute myeloid leukemia (AML) expressing the CD34+CD38− phenotype. The Isatin analog, KS99 has shown anticancer activity against multiple myeloma which may, in part, be mediated by inhibition of Bruton’s tyrosine kinase activation. Here we demonstrate that KS99 selectively targets leukemic stem cells with high aldehyde dehydrogenase activity and inhibits phosphorylation of STAT3. KS99 targeted cells co-expressing CD34, CD38, CD123, TIM-3, or CD96 immunophenotypes in AML, alone or in combination with the standard therapeutic agent cytarabine. AML with myelodysplastic-related changes was more sensitive than de novo AML with or without NPM1 mutation. KS99 treatment reduced the clonogenicity of primary human AML cells as compared to normal cord blood mononuclear cells. Downregulation of phosphorylated Bruton’s tyrosine kinase, STAT3, and aldehyde dehydrogenase was observed, suggesting interaction with KS99 as predicted through docking. KS99 with or without cytarabine showed in vivo preclinical efficacy in human and mouse AML animal models and prolonged survival. KS99 was well tolerated with overall negligible adverse effects. In conclusion, KS99 inhibits aldehyde dehydrogenase and STAT3 activities and causes cell death of leukemic stem cells, but not normal hematopoietic stem and progenitor cells.
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Affiliation(s)
- Charyguly Annageldiyev
- Department of Medicine, Division of Hematology and Oncology, Pennsylvania State University College of Medicine, Hershey, PA, USA.,Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Krishne Gowda
- Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA, USA.,Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Trupti Patel
- Department of Integrative Biotechnology, SBST, VIT Vellore, Tamilnadu, India
| | | | - Su-Fern Tan
- Department of Medicine, Division of Hematology and Oncology, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Soumya Iyer
- Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Dhimant Desai
- Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA, USA.,Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Sinisa Dovat
- Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - David J Feith
- Department of Medicine, Division of Hematology and Oncology, University of Virginia School of Medicine, Charlottesville, VA, USA.,University of Virginia Cancer Center, Charlottesville, VA, USA
| | - Thomas P Loughran
- Department of Medicine, Division of Hematology and Oncology, University of Virginia School of Medicine, Charlottesville, VA, USA.,University of Virginia Cancer Center, Charlottesville, VA, USA
| | - Shantu Amin
- Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA, USA.,Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - David Claxton
- Department of Medicine, Division of Hematology and Oncology, Pennsylvania State University College of Medicine, Hershey, PA, USA.,Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Arati Sharma
- Department of Medicine, Division of Hematology and Oncology, Pennsylvania State University College of Medicine, Hershey, PA, USA .,Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA, USA.,Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA
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48
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Yassin M, Aqaqe N, Yassin AA, van Galen P, Kugler E, Bernstein BE, Koren-Michowitz M, Canaani J, Nagler A, Lechman ER, Dick JE, Wienholds E, Izraeli S, Milyavsky M. A novel method for detecting the cellular stemness state in normal and leukemic human hematopoietic cells can predict disease outcome and drug sensitivity. Leukemia 2019; 33:2061-2077. [PMID: 30705411 DOI: 10.1038/s41375-019-0386-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2018] [Revised: 12/02/2018] [Accepted: 12/20/2018] [Indexed: 02/06/2023]
Abstract
Acute leukemia is an aggressive blood malignancy with low survival rates. A high expression of stem-like programs in leukemias predicts poor prognosis and is assumed to act in an aberrant fashion in the phenotypically heterogeneous leukemia stem cell (LSC) population. A lack of suitable genome engineering tools that can isolate LSCs based on their stemness precludes their comprehensive examination and full characterization. We hypothesized that tagging endogenous stemness-regulatory regions could generate a genome reporter for the putative leukemia stemness-state. Our analysis revealed that the ERG + 85 enhancer region can serve as a marker for stemness-state and a fluorescent lentiviral reporter was developed that can accurately recapitulate the endogenous activity. Using our novel reporter, we revealed cellular heterogeneity in several leukemia cell lines and patient-derived samples. Alterations in reporter activity were associated with transcriptomic and functional changes that were closely related to the hematopoietic stem cell (HSC) identity. Notably, the differentiation potential was skewed towards the erythro-megakaryocytic lineage. Moreover, an ERG + 85High fraction of AML cells could regenerate the original cellular heterogeneity and was enriched for LSCs. RNA-seq analysis coupled with in silico drug-screen analysis identified 4HPR as an effective inhibitor of ERG + 85High leukemia growth. We propose that further utilization of our novel molecular tool will identify crucial determinants of LSCs, thus providing a rationale for their therapeutic targeting.
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Affiliation(s)
- Muhammad Yassin
- Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv-Yafo, Israel
| | - Nasma Aqaqe
- Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv-Yafo, Israel
| | - Abed Alkader Yassin
- Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv-Yafo, Israel
| | - Peter van Galen
- Center for Cancer Research, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Eitan Kugler
- Department of Pediatric Hemato-Oncology, Schneider Children Medical Center, Petah Tikva, Israel.,The Gene Development and Environment Pediatric Research Institute, Pediatric Hemato-Oncology, Edmond and Lily Safra Children's Hospital, Chaim Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.,Department of Molecular Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv-Yafo, Israel
| | - Bradley E Bernstein
- Center for Cancer Research, Massachusetts General Hospital, Boston, MA, 02114, USA
| | | | - Jonathan Canaani
- Hematology Division, Chaim Sheba Medical Center, Tel-Hashomer, Israel
| | - Arnon Nagler
- Hematology Division, Chaim Sheba Medical Center, Tel-Hashomer, Israel
| | - Eric R Lechman
- Princess Margaret Cancer Centre, University Health Network and Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - John E Dick
- Princess Margaret Cancer Centre, University Health Network and Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Erno Wienholds
- Princess Margaret Cancer Centre, University Health Network and Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Shai Izraeli
- Department of Pediatric Hemato-Oncology, Schneider Children Medical Center, Petah Tikva, Israel.,The Gene Development and Environment Pediatric Research Institute, Pediatric Hemato-Oncology, Edmond and Lily Safra Children's Hospital, Chaim Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.,Department of Molecular Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv-Yafo, Israel
| | - Michael Milyavsky
- Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv-Yafo, Israel.
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Vassalli G. Aldehyde Dehydrogenases: Not Just Markers, but Functional Regulators of Stem Cells. Stem Cells Int 2019; 2019:3904645. [PMID: 30733805 PMCID: PMC6348814 DOI: 10.1155/2019/3904645] [Citation(s) in RCA: 209] [Impact Index Per Article: 34.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Accepted: 11/25/2018] [Indexed: 12/26/2022] Open
Abstract
Aldehyde dehydrogenase (ALDH) is a superfamily of enzymes that detoxify a variety of endogenous and exogenous aldehydes and are required for the biosynthesis of retinoic acid (RA) and other molecular regulators of cellular function. Over the past decade, high ALDH activity has been increasingly used as a selectable marker for normal cell populations enriched in stem and progenitor cells, as well as for cell populations from cancer tissues enriched in tumor-initiating stem-like cells. Mounting evidence suggests that ALDH not only may be used as a marker for stem cells but also may well regulate cellular functions related to self-renewal, expansion, differentiation, and resistance to drugs and radiation. ALDH exerts its functional actions partly through RA biosynthesis, as all-trans RA reverses the functional effects of pharmacological inhibition or genetic suppression of ALDH activity in many cell types in vitro. There is substantial evidence to suggest that the role of ALDH as a stem cell marker comes down to the specific isoform(s) expressed in a particular tissue. Much emphasis has been placed on the ALDH1A1 and ALDH1A3 members of the ALDH1 family of cytosolic enzymes required for RA biosynthesis. ALDH1A1 and ALDH1A3 regulate cellular function in both normal stem cells and tumor-initiating stem-like cells, promoting tumor growth and resistance to drugs and radiation. An improved understanding of the molecular mechanisms by which ALDH regulates cellular function will likely open new avenues in many fields, especially in tissue regeneration and oncology.
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Affiliation(s)
- Giuseppe Vassalli
- Laboratory of Cellular and Molecular Cardiology, Cardiocentro Ticino, Lugano, Switzerland
- Faculty of Biomedical Sciences, Università della Svizzera Italiana (USI), Lugano, Switzerland
- Center for Molecular Cardiology, University of Zürich, Zürich, Switzerland
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Leukemia Stem Cells in the Pathogenesis, Progression, and Treatment of Acute Myeloid Leukemia. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1143:95-128. [DOI: 10.1007/978-981-13-7342-8_5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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