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Gong Y, Fu W. Reversible role of MIR654/3P and MIR9/3P in pathogenesis of Epstein-Barr virus-negative, but not Epstein-Barr virus-positive, Burkitt lymphoma. J Leukoc Biol 2025; 117:qiae237. [PMID: 39446559 DOI: 10.1093/jleuko/qiae237] [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: 06/26/2024] [Revised: 09/13/2024] [Accepted: 10/23/2024] [Indexed: 10/26/2024] Open
Abstract
The role of MIR654 in Burkitt lymphoma (BL) and whether it impacts expression of MYC and its downstream activated MIR9 is not known. Expression of MYC, MYCN, MYCL, MIR9/3P, MIR654/5P, and MIR654/3P was assessed by quantitative reverse-transcription polymerase chain reaction in biopsy samples from Epstein-Barr virus-negative (EBV-) and EBV+ BL patients and BL cell lines. Effects of modulation of MIR9/3P and MIR654/3P on cell proliferation, apoptosis, and chemosensitivity were evaluated. Luciferase reporter assay was performed to validate the putative target of MIR654/5P. Effects of MIR9/3P and MIR654/3P on tumor burden and disease outcome were evaluated using xenograft model of BL. Expression of MYC, MYCN, and MIR9/3P was higher in all BL patient samples and cell lines. Expression of MIR654/3P was downregulated in EBV- BL patient samples and cell lines compared with either noncancer lymphoid-reactive hyperplasia or EBV+ samples and cell lines. Additionally, MIR654/3P overexpression inhibited cell proliferation, induced apoptosis, and increased chemosensitivity in EBV- BL cell lines. Luciferase reporter assay confirmed that MYC is a target of MIR654/3P in both EBV- and EBV+ BL cell lines; however, the effect of MIR654/3P-mediated targeting of MYC is overridden in EBV+ cells. Administration of MIR654/3P mimic or MIR9/3P antagomir in the xenograft model decreased tumor burden and increased survival. Combined intervention with MIR654/3P mimic and MIR9/3P antagomir had synergistic action on decreasing tumor burden and improving disease outcome. MIR654/3P, as a putative tumor suppressor in EBV- BL, collaborating with MIR9/3P might serve as a therapeutic agent to treat EBV- BL patients in combination with existing chemotherapy and immunotherapy regimes.
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Affiliation(s)
- Yu Gong
- Department of Hematology, Huainanchaoyang Hospital, No. 15 Renmin South Road, Tianjia 'an District, Huainan 232007, Anhui, China
- Department of Hematology, First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei 230022, Anhui, China
| | - Wenhua Fu
- Cancer Center, Huainanchaoyang Hospital, No. 15 Renmin South Road, Tianjia 'an District, Huainan 232007, Anhui, China
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2
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Fang H, Wang W, Medeiros LJ. Burkitt lymphoma. Hum Pathol 2025; 156:105703. [PMID: 39662784 DOI: 10.1016/j.humpath.2024.105703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Revised: 12/02/2024] [Accepted: 12/08/2024] [Indexed: 12/13/2024]
Abstract
Burkitt lymphoma is a mature aggressive B-cell neoplasm with distinctive clinical and morphologic features, a germinal center B-cell immunophenotype, a high proliferation index and MYC rearrangement with an immunoglobulin gene partner. Initially described in equatorial Africa by a surgeon, Denis Burkitt, African (endemic) Burkitt lymphoma was the first neoplasm shown to be associated with a virus, Epstein-Barr virus (EBV), and the first neoplasm shown to be associated with a chromosomal translocation, IGH::MYC. In this article, we provide a brief historical introduction of Burkitt lymphoma, followed by a review of all aspects of this neoplasm including pathogenesis, clinical presentation, morphology, immunophenotype, cytogenetics and molecular findings. We also provide recent updates of this entity, including advances in our understanding of molecular pathogenesis of Burkitt lymphoma and the recent proposal in the current World Health Organization classification that the traditional epidemiologic variants of Burkitt lymphoma are better replaced by presence or absence of EBV infection. We also discuss the differential diagnosis of Burkitt lymphoma and how this neoplasm can be distinguished from reactive conditions and other aggressive B-cell lymphomas/leukemias. Given its very rapid growth and the unique treatment approach employed to treat these patients, it is important to recognize Burkitt lymphoma to facilitate appropriate therapy.
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Affiliation(s)
- Hong Fang
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Wei Wang
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - L Jeffrey Medeiros
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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3
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Zhou Y, Lou J, Tian Y, Ding J, Wang X, Tang B. How lactate affects immune strategies in lymphoma. Front Mol Biosci 2024; 11:1480884. [PMID: 39464313 PMCID: PMC11502318 DOI: 10.3389/fmolb.2024.1480884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 09/30/2024] [Indexed: 10/29/2024] Open
Abstract
Tumor cells undergo metabolic reprogramming through shared pathways, resulting in a hypoxic, acidic, and highly permeable internal tumor microenvironment (TME). Lactate, once only regarded as a waste product of glycolysis, has an inseparable dual role with tumor immunity. It can not only provide a carbon source for immune cells to enhance immunity but also help the immune escape through a variety of ways. Lymphoma also depends on the proliferation signal of TME. This review focuses on the dynamic process of lactate metabolism and immune function changes in lymphoma and aims to comprehensively summarize and explore which genes, transcription factors, and pathways affect the biological changes and functions of immune cells. To deeply understand the complex and multifaceted role of lactate metabolism and immunity in lymphoma, the combination of lactate targeted therapy and classical immunotherapy will be a promising development direction in the future.
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Affiliation(s)
- Yuehan Zhou
- Department of Hematology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Jinzhan Lou
- Department of Hematology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yuqin Tian
- Department of Hematology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Jinlei Ding
- Department of Thoracic Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xiaobo Wang
- Department of Hematology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Bo Tang
- Department of Hematology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
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Tao S, Huang Q, Zhou W, Chen J, Man Y, Chen L, Chen Y. FOXO3 suppresses lymphoma progression through promoting miR-34b/HSPG2 axis. Int J Lab Hematol 2024; 46:885-893. [PMID: 38775786 DOI: 10.1111/ijlh.14310] [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: 11/24/2023] [Accepted: 05/02/2024] [Indexed: 11/20/2024]
Abstract
BACKGROUND Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma, which caused many patients to lose their precious lives. FOXO3 was a suppressor in various cancers, however, the role and mechanism of FOXO3 in DLBCL remain unclear. METHODS Bioinformatics analysis was used to offer information FOXO3 expression and its expression for prognosis of DLBCL patients. The abundance of genes and proteins was evaluated using RT-qPCR and western blot. Cell proliferation and apoptosis was detected by CCK-8 and flow cytometry. The interactions among FOXO3, miR-34b, and HSPG2 were predicted by TransmiR and Starbase and validated using dual luciferase reporter assay, ChIP assay, and RIP assay. RESULTS Our findings revealed that FOXO3 expression was abnormally declined in DLBCL cells. FOXO3 upregulation restrained cell proliferation and promoted cell apoptosis of DLBCL cells, while miR-34b inhibitor eliminated these influences. Similarly, miR-34b mimic suppressed malignant behaviors of DLBCL cells, which were abolished by HSPG2 overexpression. Mechanically, FOXO3 induced miR-34b expression through interacting with miR-34b promoter and HSPG2 was a targeted gene of miR-34b. CONCLUSION FOXO3 attenuated the capability of cell proliferation and promoted cell apoptosis rate of DLBCL cells through affecting miR-34b/HSPG2 axis, therefore inhibiting DLBCL progression.
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Affiliation(s)
- Shi Tao
- Department of Hematology, Hainan Province Clinical Medical Center, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province, China
| | - Qianlei Huang
- Department of Hematology, Hainan Province Clinical Medical Center, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province, China
| | - Weilun Zhou
- Department of Hematology, Hainan Province Clinical Medical Center, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province, China
| | - Jing Chen
- School of Preventive Medicine, Hainan Medical University, Haikou, Hainan Province, China
| | - Yuxuan Man
- The First School of Clinical Medicine, Hainan Medical University, Haikou, Hainan Province, China
| | - Lang Chen
- School of Preventive Medicine, Hainan Medical University, Haikou, Hainan Province, China
| | - Yu Chen
- Department of Hematology, Hainan Province Clinical Medical Center, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province, China
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Zhang N, Duan YL, Zhou CJ, Jin L, Yang J, Huang S, Zhang M, Li N. [Clinical study of mature B-cell lymphoma in 11 children with chromosome 11 long-arm abnormalities]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2023; 44:924-929. [PMID: 38185522 PMCID: PMC10753258 DOI: 10.3760/cma.j.issn.0253-2727.2023.11.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Indexed: 01/09/2024]
Abstract
Objective: To explore the clinical, pathological, diagnostic, treatment, and prognostic features of children with mature B-cell lymphoma (MBCL) . Methods: This retrospective study included pediatric patients with MBCL with chromosome 11 long-arm abnormalities who were diagnosed and treated at our hospital from December 2018 to February 2023. Results: Among the 11 pediatric patients with MBCL, nine were male and two were female, with a median age of 9 (2-13) years and a median disease course of 1.8 (0.5-24) months. The clinical manifestations were cervical lymph node enlargement in four patients, nasal congestion and snoring in four patients, abdominal pain in two patients, and difficulty breathing in one patient. There were seven cases of Burkitt's lymphoma, two of follicular lymphoma, and two of advanced B-cell lymphoma according to the pathological morphology examination. No patients had central nervous system or bone marrow involvement, and no extensive metastasis was observed on B-ultrasound or positron emission tomography-computed tomography (PET/CT). One patient had a huge tumor lesion. The Revised International Pediatric Non-Hodgkin Lymphoma Staging System classified four patients as stage Ⅱ, five as stage Ⅲ, and two as stage Ⅳ. 11q probe detection showed five cases of 11q gain, three of 11q loss, and three of both gain and loss. FISH showed positive MYC expression in three patients, including eight with advanced B-cell lymphoma with 11q abnormalities and three with Burkitt's lymphoma with 11q abnormalities. According to the 2019 edition of the National Health Commission's diagnostic and treatment guidelines for invasive MBCL in children, one patient was classified as Group A, two as Group B, and eight as Group C. Early evaluation of the efficacy showed complete remission. After mid-term evaluation, the intensity of chemotherapy was reduced in Group B and Group C. Among two cases of chemotherapy, the remaining nine cases had a median follow-up of 32 (6-45) months, and none had event-related survival. Conclusion: The incidence of MBCL with 11q abnormalities in children is low, clinical symptoms are mild, and progression is slow. The absence of MYC, BCL2, BCL6 rearrangements, C-MYC negative and 11q abnormalities on FISH is an important diagnostic indicator, and reducing the intensity of chemotherapy can improve prognosis.
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Affiliation(s)
- N Zhang
- Medical Oncology Department, Pediatric Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing Key Laboratory of Pediatric Hematology Oncology, Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing 100045, China
| | - Y L Duan
- Medical Oncology Department, Pediatric Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing Key Laboratory of Pediatric Hematology Oncology, Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing 100045, China
| | - C J Zhou
- Medical Oncology Department, Pediatric Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Department of Pathology
| | - L Jin
- Medical Oncology Department, Pediatric Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing Key Laboratory of Pediatric Hematology Oncology, Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing 100045, China
| | - J Yang
- Medical Oncology Department, Pediatric Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing Key Laboratory of Pediatric Hematology Oncology, Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing 100045, China
| | - S Huang
- Medical Oncology Department, Pediatric Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing Key Laboratory of Pediatric Hematology Oncology, Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing 100045, China
| | - M Zhang
- Medical Oncology Department, Pediatric Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing Key Laboratory of Pediatric Hematology Oncology, Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing 100045, China
| | - N Li
- Medical Oncology Department, Pediatric Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing Key Laboratory of Pediatric Hematology Oncology, Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing 100045, China
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6
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Wang Y, Liu D, Zhang X, Zhang M, Li S, Feng X, Dong M, Ma S, Qian S, Wang Z, Zhang Y, Wang P, Mei S, Chen Q. MYC overexpression but not MYC/BCL2 double expression predicts survival in bulky mass diffuse large B-cell lymphoma patients. Cancer Med 2023; 12:18568-18577. [PMID: 37641492 PMCID: PMC10557898 DOI: 10.1002/cam4.6463] [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: 07/31/2023] [Accepted: 08/06/2023] [Indexed: 08/31/2023] Open
Abstract
PURPOSE The prognostic factors for diffuse large B-cell lymphoma (DLBCL) have been fully explored, but prognostic information for bulky mass DLBCL patients is limited. This study aimed to analyze the prognostic value of MYC protein expression and other biological parameters in bulky mass DLBCL patients. METHODS We defined a bulky mass as a maximum tumor diameter ≥7.5 cm and studied 227 patients with de novo bulky mass DLBCL. RESULTS In all patients with bulky mass DLBCL, the 1-year and 3-year OS rates were 72.7% and 57.1%, respectively, and the 1-year and 3-year PFS rates were 52.0% and 42.5%, respectively. The MYC overexpression group (n = 140) showed significantly worse overall survival (OS; p = 0.019) and progression-free survival (PFS; p = 0.001) than the non-MYC overexpression group (n = 87). Subgroup analyses demonstrated that the MYC overexpression group was associated with inferior OS and PFS in the subgroups with the International Prognostic Index score of 3-5 (OS: p = 0.011; PFS: p < 0.001), Ann Arbor stage 3-4 (OS: p = 0.014; PFS: p < 0.001) and GCB subtype (OS: p = 0.014; PFS: p = 0.010). Consolidation radiotherapy improved OS and PFS in patients with bulky mass DLBCL (OS: p = 0.008; PFS: p = 0.004) as well as in those with MYC overexpression (OS: p = 0.001; PFS: p = 0.001). The prognostic value of MYC overexpression was maintained in a multivariate model adjusted for the International Prognostic Index. CONCLUSION MYC overexpression is a poor predictor for bulky mass DLBCL patients. Consolidation radiotherapy for residual disease after induction therapy may improve outcomes for patients with bulky mass DLBCL.
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Affiliation(s)
- Yanjie Wang
- Department of Oncology, Henan Province Lymphoma Treatment CenterThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Donglin Liu
- Department of Oncology, Henan Province Lymphoma Treatment CenterThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Xudong Zhang
- Department of Oncology, Henan Province Lymphoma Treatment CenterThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Mingzhi Zhang
- Department of Oncology, Henan Province Lymphoma Treatment CenterThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Shenglei Li
- Department of PathologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Xiaoyan Feng
- Department of Oncology, Henan Province Lymphoma Treatment CenterThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Meng Dong
- Department of Oncology, Henan Province Lymphoma Treatment CenterThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Shanshan Ma
- Department of Oncology, Henan Province Lymphoma Treatment CenterThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Siyu Qian
- Department of Oncology, Henan Province Lymphoma Treatment CenterThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Zeyuan Wang
- Department of PathologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Yue Zhang
- Department of Oncology, Henan Province Lymphoma Treatment CenterThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Pengyuan Wang
- Department of Medical OncologyXuchang Central HospitalXuchangChina
| | - Shuhao Mei
- Department of HematologyXuchang Central HospitalXuchangChina
| | - Qingjiang Chen
- Department of Oncology, Henan Province Lymphoma Treatment CenterThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
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7
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Pang Y, Lu T, Xu-Monette ZY, Young KH. Metabolic Reprogramming and Potential Therapeutic Targets in Lymphoma. Int J Mol Sci 2023; 24:5493. [PMID: 36982568 PMCID: PMC10052731 DOI: 10.3390/ijms24065493] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 03/09/2023] [Accepted: 03/10/2023] [Indexed: 03/17/2023] Open
Abstract
Lymphoma is a heterogeneous group of diseases that often require their metabolism program to fulfill the demand of cell proliferation. Features of metabolism in lymphoma cells include high glucose uptake, deregulated expression of enzymes related to glycolysis, dual capacity for glycolytic and oxidative metabolism, elevated glutamine metabolism, and fatty acid synthesis. These aberrant metabolic changes lead to tumorigenesis, disease progression, and resistance to lymphoma chemotherapy. This metabolic reprogramming, including glucose, nucleic acid, fatty acid, and amino acid metabolism, is a dynamic process caused not only by genetic and epigenetic changes, but also by changes in the microenvironment affected by viral infections. Notably, some critical metabolic enzymes and metabolites may play vital roles in lymphomagenesis and progression. Recent studies have uncovered that metabolic pathways might have clinical impacts on the diagnosis, characterization, and treatment of lymphoma subtypes. However, determining the clinical relevance of biomarkers and therapeutic targets related to lymphoma metabolism is still challenging. In this review, we systematically summarize current studies on metabolism reprogramming in lymphoma, and we mainly focus on disorders of glucose, amino acids, and lipid metabolisms, as well as dysregulation of molecules in metabolic pathways, oncometabolites, and potential metabolic biomarkers. We then discuss strategies directly or indirectly for those potential therapeutic targets. Finally, we prospect the future directions of lymphoma treatment on metabolic reprogramming.
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Affiliation(s)
- Yuyang Pang
- Division of Hematopathology, Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA
- Department of Hematology, Ninth People’s Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China
| | - Tingxun Lu
- Division of Hematopathology, Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA
- Duke Cancer Institute, Durham, NC 27710, USA
| | - Zijun Y. Xu-Monette
- Division of Hematopathology, Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA
- Duke Cancer Institute, Durham, NC 27710, USA
| | - Ken H. Young
- Division of Hematopathology, Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA
- Duke Cancer Institute, Durham, NC 27710, USA
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Tumor Immune Microenvironment in Lymphoma: Focus on Epigenetics. Cancers (Basel) 2022; 14:cancers14061469. [PMID: 35326620 PMCID: PMC8946119 DOI: 10.3390/cancers14061469] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 02/23/2022] [Accepted: 03/11/2022] [Indexed: 02/06/2023] Open
Abstract
Lymphoma is a neoplasm arising from B or T lymphocytes or natural killer cells characterized by clonal lymphoproliferation. This tumor comprises a diverse and heterogeneous group of malignancies with distinct clinical, histopathological, and molecular characteristics. Despite advances in lymphoma treatment, clinical outcomes of patients with relapsed or refractory disease remain poor. Thus, a deeper understanding of molecular pathogenesis and tumor progression of lymphoma is required. Epigenetic alterations contribute to cancer initiation, progression, and drug resistance. In fact, over the past decade, dysregulation of epigenetic mechanisms has been identified in lymphomas, and the knowledge of the epigenetic aberrations has led to the emergence of the promising epigenetic therapy field in lymphoma tumors. However, epigenetic aberrations in lymphoma not only have been found in tumor cells, but also in cells from the tumor microenvironment, such as immune cells. Whereas the epigenetic dysregulation in lymphoma cells is being intensively investigated, there are limited studies regarding the epigenetic mechanisms that affect the functions of immune cells from the tumor microenvironment in lymphoma. Therefore, this review tries to provide a general overview of epigenetic alterations that affect both lymphoma cells and infiltrating immune cells within the tumor, as well as the epigenetic cross-talk between them.
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9
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Kaller M, Hünten S, Siemens H, Hermeking H. Analysis of the p53/microRNA Network in Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1385:187-228. [DOI: 10.1007/978-3-031-08356-3_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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10
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Yazarlou F, Kadkhoda S, Ghafouri-Fard S. Emerging role of let-7 family in the pathogenesis of hematological malignancies. Biomed Pharmacother 2021; 144:112334. [PMID: 34656064 DOI: 10.1016/j.biopha.2021.112334] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 10/04/2021] [Accepted: 10/10/2021] [Indexed: 12/30/2022] Open
Abstract
Let-7 includes a family of miRNA which are implicated in the developmental processes as well as carcinogenesis. This miRNA family has been shown to influence pathogenesis of a variety of hematological malignancies through changing expression of a number of oncogenic pathways, particularly those related with MYC. Expression of these miRNAs has been found to be different between distinct hematological malignancies or even between cytogenetically-defined subgroups of a certain malignancy. In the current review, we summarize the data regarding biogenesis, genomic locations, targets and regulatory network of this miRNA family in the context of hematological malignancies.
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Affiliation(s)
- Fatemeh Yazarlou
- Department of Medical Genetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Sepideh Kadkhoda
- Department of Medical Genetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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11
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Pizzi M, Sabattini E, Parente P, Bellan A, Doglioni C, Lazzi S. Gastrointestinal lymphoproliferative lesions: a practical diagnostic approach. Pathologica 2021; 112:227-247. [PMID: 33179624 PMCID: PMC7931576 DOI: 10.32074/1591-951x-161] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 06/29/2020] [Indexed: 12/15/2022] Open
Abstract
The gastrointestinal tract (GI) is the primary site of lymphoproliferative lesions, spanning from reactive lymphoid hyperplasia to overt lymphoma. The diagnosis of these diseases is challenging and an integrated approach based on clinical, morphological, immunohistochemical and molecular data is needed. To reach to confident conclusions, a stepwise approach is highly recommended. Histological evaluation should first assess the benign versus neoplastic nature of a given lymphoid infiltrate. Morphological and phenotypic analyses should then be applied to get to a definite diagnosis. This review addresses the key histological features and diagnostic workup of the most common GI non-Hodgkin lymphomas (NHLs). Differential diagnoses and possible pitfalls are discussed by considering distinct groups of lesions (i.e. small to medium B-cell NHLs; medium to large B-cell NHLs; T-cell NHLs; and mimickers of Hodgkin lymphoma). The key clinical and epidemiological features of each entity are also described.
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Affiliation(s)
- Marco Pizzi
- General Pathology and Cytopathology Unit, Department of Medicine - DIMED, University of Padova, Italy
| | - Elena Sabattini
- Hematopathology Unit, Sant'Orsola University Hospital, Bologna (BO), Italy
| | - Paola Parente
- Pathology Unit, Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy
| | - Alberto Bellan
- Department of Pathology, ULSS6, Camposampiero Hospital, Camposampiero (PD), Italy
| | - Claudio Doglioni
- Department of Pathology, University Vita-Salute San Raffaele, IRCCS San Raffaele Hospital, Milano, Italy
| | - Stefano Lazzi
- Department of Medical Biotechnology, Section of Pathology, University of Siena, Italy
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12
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The Role of Non-Coding RNAs in the Regulation of the Proto-Oncogene MYC in Different Types of Cancer. Biomedicines 2021; 9:biomedicines9080921. [PMID: 34440124 PMCID: PMC8389562 DOI: 10.3390/biomedicines9080921] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 07/25/2021] [Accepted: 07/28/2021] [Indexed: 01/17/2023] Open
Abstract
Alterations in the expression level of the MYC gene are often found in the cells of various malignant tumors. Overexpressed MYC has been shown to stimulate the main processes of oncogenesis: uncontrolled growth, unlimited cell divisions, avoidance of apoptosis and immune response, changes in cellular metabolism, genomic instability, metastasis, and angiogenesis. Thus, controlling the expression of MYC is considered as an approach for targeted cancer treatment. Since c-Myc is also a crucial regulator of many cellular processes in healthy cells, it is necessary to find ways for selective regulation of MYC expression in tumor cells. Many recent studies have demonstrated that non-coding RNAs play an important role in the regulation of the transcription and translation of this gene and some RNAs directly interact with the c-Myc protein, affecting its stability. In this review, we summarize current data on the regulation of MYC by various non-coding RNAs that can potentially be targeted in specific tumor types.
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13
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Drillis G, Goulielmaki M, Spandidos DA, Aggelaki S, Zoumpourlis V. Non-coding RNAs (miRNAs and lncRNAs) and their roles in lymphogenesis in all types of lymphomas and lymphoid malignancies. Oncol Lett 2021; 21:393. [PMID: 33777216 PMCID: PMC7988683 DOI: 10.3892/ol.2021.12654] [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: 12/16/2020] [Accepted: 02/26/2021] [Indexed: 12/16/2022] Open
Abstract
Contemporary developments in molecular biology have been combined with discoveries on the analysis of the role of all non-coding RNAs (ncRNAs) in human diseases, particularly in cancer, by examining their roles in cells. Currently, included among these common types of cancer, are all the lymphomas and lymphoid malignancies, which represent a diverse group of neoplasms and malignant disorders. Initial data suggest that non-coding RNAs, particularly long ncRNAs (lncRNAs), play key roles in oncogenesis and that lncRNA-mediated biology is an important key pathway to cancer progression. Other non-coding RNAs, termed microRNAs (miRNAs or miRs), are very promising cancer molecular biomarkers. They can be detected in tissues, cell lines, biopsy material and all biological fluids, such as blood. With the number of well-characterized cancer-related lncRNAs and miRNAs increasing, the study of the roles of non-coding RNAs in cancer is bringing forth new hypotheses of the biology of cancerous cells. For the first time, to the best of our knowledge, the present review provides an up-to-date summary of the recent literature referring to all diagnosed ncRNAs that mediate the pathogenesis of all types of lymphomas and lymphoid malignancies.
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Affiliation(s)
- Georgios Drillis
- 1st Internal Medicine Clinic, Medical School, Laiko University Hospital of Athens, 115 27 Athens, Greece
| | - Maria Goulielmaki
- Biomedical Applications Unit, Institute of Chemical Biology, National Hellenic Research Foundation (NHRF), 116 35 Athens, Greece
| | - Demetrios A Spandidos
- Laboratory of Clinical Virology, Medical School, University of Crete, 71003 Heraklion, Greece
| | - Sofia Aggelaki
- Oncology Unit, Medical School, University of Crete, 71003 Heraklion, Greece
| | - Vassilios Zoumpourlis
- Biomedical Applications Unit, Institute of Chemical Biology, National Hellenic Research Foundation (NHRF), 116 35 Athens, Greece
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14
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Aberrant Methylation of miR-34b and IL-12B mRNA Promoters Contributes to the Reduced Severity of Ankylosing Spondylitis. Biochem Genet 2021; 59:714-730. [PMID: 33512625 DOI: 10.1007/s10528-020-10023-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 12/12/2020] [Indexed: 10/22/2022]
Abstract
DNA methylation of Interleukin-12B (IL-12B) and miR-34b was proved to affect the expression of IL-12B and miR-34b, which were found to be involved in the pathogenesis of ankylosing spondylitis (AS). However, the molecular mechanisms underlying the role of IL-12B and miR-34b in AS remain to be explored. AS patients were divided into four groups according to their status of DNA methylation of miR-34b and IL-12B by bisulfite sequencing: HYPER-miR-34b + HYPO-IL-12B, HYPER-miR-34b + HYPER-IL-12B, HYPO-miR-34b + HYPER-IL-12B and HYPO-miR-34b + HYPO-IL-12B groups. Functional indicators were examined for patients with different status of DNA methylation in their miR-34b and IL-12B promoters. QPCR was performed to examine the expression of miR-34b and IL-12B mRNA under different conditions. ELISA was used to measure the expression of IL-12B p40 in the peripheral blood. Western blot was used to analyze the expression of IL-12B proteins. Luciferase assay was carried out to explore the suppressive role of miR-34b in IL-12B expression. The level of Ankylosing Spondylitis Disease Activity Score with C-reactive protein (ASDAS-CRP) was gradually increased in HYPER-miR-34b + HYPO-IL-12B,HYPER-miR-34b + HYPER-IL-12B,HYPO-miR-34b + HYPER-IL-12B and HYPO-miR-34b + HYPO-IL-12B groups, whereas the levels of Bath Ankylosing Spondylitis Functional Index (BASFI) and Bath Ankylosing Spondylitis Metrology Index (BASMI) were significantly elevated in the HYPO-miR-34b + HYPO-IL-12B group and diminished in the HYPER-miR-34b + HYPO-IL-12B group. The expression of miR-34b in the PBMCs and peripheral blood was remarkably higher in the HYPER-miR-34b + HYPO-IL-12B and HYPER-miR-34b + HYPER-IL-12B groups, whereas the expression of IL-12B was gradually decreased in the HYPER-miR-34b + HYPO-IL-12B, HYPER-miR-34b + HYPER-IL-12B, HYPO-miR-34b + HYPER-IL-12B and HYPO-miR-34b + HYPO-IL-12B groups. Luciferase assays with the transfection of miR-34b precursors suggested that miR-34b strongly suppressed the expression of IL-12B in THP-1 cells. In conclusion, our study demonstrated that hypermethylated miR-34b promoter led to evident upregulation of miR-34b, thus inhibiting the expression of IL-12B and alleviated the severity of ankylosing spondylitis by reducing the levels of factors including ASDAS-CRP, BASFI and BASMI.
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15
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Lauw MIS, Lucas CHG, Ohgami RS, Wen KW. Primary Central Nervous System Lymphomas: A Diagnostic Overview of Key Histomorphologic, Immunophenotypic, and Genetic Features. Diagnostics (Basel) 2020; 10:diagnostics10121076. [PMID: 33322508 PMCID: PMC7764608 DOI: 10.3390/diagnostics10121076] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/08/2020] [Accepted: 12/09/2020] [Indexed: 02/07/2023] Open
Abstract
Primary central nervous system lymphoma (PCNSL) is a rare form of extranodal non-Hodgkin lymphoma that primarily arises in the brain, spinal cord, leptomeninges, and vitreoretinal compartment of the eye. The term is sometimes used interchangeably with primary central nervous system diffuse large B-cell lymphoma (PCNS DLBCL) because DLBCL comprises a great majority (90–95%) of PCNSL. Although rare, other types of lymphomas can be seen in the central nervous system (CNS), and familiarity with these entities will help their recognition and further workup in order to establish the diagnosis. The latter is especially important in the case of PCNSL where procurement of diagnostic specimen is often challenging and yields scant tissue. In this review, we will discuss the most common types of primary lymphomas that can be seen in the CNS with emphasis on the diagnostic histomorphologic, immunophenotypic, and molecular genetic features. The differential diagnostic approach to these cases and potential pitfalls will also be discussed.
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Affiliation(s)
- Marietya I. S. Lauw
- Department of Pathology, University of California, San Francisco, CA 94143, USA; (C.-H.G.L.); (R.S.O.); (K.W.W.)
- Correspondence:
| | - Calixto-Hope G. Lucas
- Department of Pathology, University of California, San Francisco, CA 94143, USA; (C.-H.G.L.); (R.S.O.); (K.W.W.)
| | - Robert S. Ohgami
- Department of Pathology, University of California, San Francisco, CA 94143, USA; (C.-H.G.L.); (R.S.O.); (K.W.W.)
- Department of Pathology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158, USA
| | - Kwun Wah Wen
- Department of Pathology, University of California, San Francisco, CA 94143, USA; (C.-H.G.L.); (R.S.O.); (K.W.W.)
- Department of Pathology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158, USA
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16
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Chebly A, Chouery E, Ropio J, Kourie HR, Beylot-Barry M, Merlio JP, Tomb R, Chevret E. Diagnosis and treatment of lymphomas in the era of epigenetics. Blood Rev 2020; 48:100782. [PMID: 33229141 DOI: 10.1016/j.blre.2020.100782] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 08/05/2020] [Accepted: 10/15/2020] [Indexed: 12/19/2022]
Abstract
Lymphomas represent a heterogeneous group of cancers characterized by clonal lymphoproliferation. Over the past decades, frequent epigenetic dysregulations have been identified in hematologic malignancies including lymphomas. Many of these impairments occur in genes with established roles and well-known functions in the regulation and maintenance of the epigenome. In hematopoietic cells, these dysfunctions can result in abnormal DNA methylation, erroneous chromatin state and/or altered miRNA expression, affecting many different cellular functions. Nowadays, it is evident that epigenetic dysregulations in lymphoid neoplasms are mainly caused by genetic alterations in genes encoding for enzymes responsible for histone or chromatin modifications. We summarize herein the recent epigenetic modifiers findings in lymphomas. We focus also on the most commonly mutated epigenetic regulators and emphasize on actual epigenetic therapies.
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Affiliation(s)
- Alain Chebly
- Bordeaux University, INSERM U1053 Bordeaux Research in Translational Oncology (BaRITOn), Cutaneous Lymphoma Oncogenesis Team, F-33000 Bordeaux, France; Saint Joseph University, Faculty of Medicine, Medical Genetics Unit (UGM), Beirut, Lebanon
| | - Eliane Chouery
- Saint Joseph University, Faculty of Medicine, Medical Genetics Unit (UGM), Beirut, Lebanon
| | - Joana Ropio
- Bordeaux University, INSERM U1053 Bordeaux Research in Translational Oncology (BaRITOn), Cutaneous Lymphoma Oncogenesis Team, F-33000 Bordeaux, France; Porto University, Institute of Biomedical Sciences of Abel Salazar, 4050-313 Porto, Instituto de Investigação e Inovação em Saúde, 4200-135 Porto, Institute of Molecular Pathology and Immunology (Ipatimup), Cancer Biology group, 4200-465 Porto, Portugal
| | - Hampig Raphael Kourie
- Saint Joseph University, Faculty of Medicine, Medical Genetics Unit (UGM), Beirut, Lebanon; Saint Joseph University, Faculty of Medicine, Hematology-Oncology Department, Beirut, Lebanon
| | - Marie Beylot-Barry
- Bordeaux University, INSERM U1053 Bordeaux Research in Translational Oncology (BaRITOn), Cutaneous Lymphoma Oncogenesis Team, F-33000 Bordeaux, France; Bordeaux University Hospital Center, Dermatology Department, 33000 Bordeaux, France
| | - Jean-Philippe Merlio
- Bordeaux University, INSERM U1053 Bordeaux Research in Translational Oncology (BaRITOn), Cutaneous Lymphoma Oncogenesis Team, F-33000 Bordeaux, France; Bordeaux University Hospital Center, Tumor Bank and Tumor Biology Laboratory, 33600 Pessac, France
| | - Roland Tomb
- Saint Joseph University, Faculty of Medicine, Medical Genetics Unit (UGM), Beirut, Lebanon; Saint Joseph University, Faculty of Medicine, Dermatology Department, Beirut, Lebanon
| | - Edith Chevret
- Bordeaux University, INSERM U1053 Bordeaux Research in Translational Oncology (BaRITOn), Cutaneous Lymphoma Oncogenesis Team, F-33000 Bordeaux, France.
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17
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Bailey NG, Elenitoba-Johnson KSJ. Impact of Genetics on Mature Lymphoid Leukemias and Lymphomas. Cold Spring Harb Perspect Med 2020; 10:cshperspect.a035444. [PMID: 31932467 DOI: 10.1101/cshperspect.a035444] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Recurrent genetic aberrations have long been recognized in mature lymphoid leukemias and lymphomas. As conventional karyotypic and molecular cloning techniques evolved in the 1970s and 1980s, multiple cytogenetic aberrations were identified in lymphomas, often balanced translocations that juxtaposed oncogenes to the immunoglobulin (IG) or T-cell receptor (TR) loci, leading to dysregulation. However, genetic characterization and classification of lymphoma by conventional cytogenetic methods is limited by the infrequent occurrence of recurrent karyotypic abnormalities in many lymphoma subtypes and by the frequent difficulty in growing clinical lymphoma specimens in culture to obtain informative karyotypes. As higher-resolution genomic techniques developed, such as array comparative genomic hybridization and fluorescence in situ hybridization, many recurrent copy number changes were identified in lymphomas, and copy number assessment of interphase cells became part of routine clinical practice for a subset of diseases. Platforms to globally examine mRNA expression led to major insights into the biology of several lymphomas, although these techniques have not gained widespread application in routine clinical settings. With the advent of next-generation sequencing (NGS) techniques in the early 2000s, numerous insights into the genetic landscape of lymphomas were obtained. In contrast to the myeloid malignancies, most common lymphomas exhibit an at least somewhat mutationally complex genome, with few single driver mutations in the majority of patients. However, many recurrently mutated pathways have been identified across lymphoma subtypes, informing targeted therapeutic approaches that are beginning to make meaningful changes in the treatment of lymphoma. In addition to the ability to identify possible therapeutic targets, NGS techniques are highly amenable to the tracking of residual lymphoma following therapy, because of the presence of unique genetic "fingerprints" in lymphoma cells due to V(D)-J recombination at the antigen receptor loci. This review will provide an overview of the impact of novel genetic technologies on lymphoma classification, biology, and therapy.
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Affiliation(s)
- Nathanael G Bailey
- Division of Hematopathology, Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
| | - Kojo S J Elenitoba-Johnson
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19102, USA
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18
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Li J, Zou J, Wan X, Sun C, Peng F, Chu Z, Hu Y. The Role of Noncoding RNAs in B-Cell Lymphoma. Front Oncol 2020; 10:577890. [PMID: 33194698 PMCID: PMC7645065 DOI: 10.3389/fonc.2020.577890] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 08/20/2020] [Indexed: 12/19/2022] Open
Abstract
In recent years, emerging evidence has suggested that noncoding RNAs (ncRNAs) participate in nearly every aspect of biological processes and play a crucial role in the genesis and progression of numerous tumors, including B-cell lymphoma. The exploration of ncRNA dysregulations and their functions in B-cell lymphoma provides new insights into lymphoma pathogenesis and is essential for indicating future clinical trials and optimizing the diagnostic and therapeutic strategies. In this review, we summarize the role of ncRNAs in B-cell lymphoma and discuss their potential in clinical applications.
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Affiliation(s)
- Jingwen Li
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Zou
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoyue Wan
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chunyan Sun
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Collaborative Innovation Center of Hematology, Huazhong University of Science and Technology, Wuhan, China
| | - Fei Peng
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhangbo Chu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yu Hu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Collaborative Innovation Center of Hematology, Huazhong University of Science and Technology, Wuhan, China
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19
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Jang H, Park S, Kim J, Kim JH, Kim SY, Cho S, Park SG, Park BC, Kim S, Kim JH. The Tumor Suppressor, p53, Negatively Regulates Non-Canonical NF-κB Signaling through miRNAInduced Silencing of NF-κB-Inducing Kinase. Mol Cells 2020; 43:23-33. [PMID: 31870133 PMCID: PMC6999715 DOI: 10.14348/molcells.2019.0239] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 11/26/2019] [Accepted: 11/27/2019] [Indexed: 01/06/2023] Open
Abstract
NF-κB signaling through both canonical and non-canonical pathways plays a central role in immune responses and inflammation. NF-κB-inducing kinase (NIK) stabilization is a key step in activation of the non-canonical pathway and its dysregulation implicated in various hematologic malignancies. The tumor suppressor, p53, is an established cellular gatekeeper of proliferation. Abnormalities of the TP53 gene have been detected in more than half of all human cancers. While the non-canonical NF-κB and p53 pathways have been explored for several decades, no studies to date have documented potential cross-talk between these two cancer-related mechanisms. Here, we demonstrate that p53 negatively regulates NIK in an miRNA-dependent manner. Overexpression of p53 decreased the levels of NIK, leading to inhibition of the non-canonical NF-κB pathway. Conversely, its knockdown led to increased levels of NIK, IKKα phosphorylation, and p100 processing. Additionally, miR-34b induced by nutlin-3 directly targeted the coding sequences (CDS) of NIK. Treatment with anti-miR-34b-5p augmented NIK levels and subsequent non-canonical NF-κB signaling. Our collective findings support a novel cross-talk mechanism between non-canonical NF-κB and p53.
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Affiliation(s)
- Hanbit Jang
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141,
Korea
- Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141,
Korea
| | - Seulki Park
- Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141,
Korea
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113,
Korea
| | - Jaehoon Kim
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141,
Korea
| | - Jong Hwan Kim
- Personalized Genomic Medicine Research Center, KRIBB, Daejeon 34141,
Korea
| | - Seon-Young Kim
- Personalized Genomic Medicine Research Center, KRIBB, Daejeon 34141,
Korea
| | - Sayeon Cho
- College of Pharmacy, Chung-Ang University, Seoul 06974,
Korea
| | - Sung Goo Park
- Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141,
Korea
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113,
Korea
| | - Byoung Chul Park
- Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141,
Korea
- Department of Proteome Structural Biology, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113,
Korea
| | - Sunhong Kim
- Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141,
Korea
- Department of Bio-Molecular Science, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113,
Korea
| | - Jeong-Hoon Kim
- Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141,
Korea
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113,
Korea
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20
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Ndede I, Mining SK, Patel K, Wanjala FM, Tenge C. Immunoglobulin heavy variable (IgHV) gene mutation and micro-RNA expression in Burkitt's lymphoma at Moi Teaching and Referral Hospital in Western Kenya. Afr Health Sci 2019; 19:3242-3248. [PMID: 32127902 PMCID: PMC7040314 DOI: 10.4314/ahs.v19i4.48] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
INTRODUCTION Burkitt's lymphoma (BL) is a virus associated childhood B-cell cancer common in Eastern Africa. Continued survival of B-cells in germinal centres depend on expression of high affinity immunoglobulins (Ig) to complementary antigens by somatic hypermutation of Ig genes. Cellular microRNAs, non-coding RNAs have been reported to play role in cell cycle regulation. Both viral antigen dependent mutation and micro-RNA expression maybe involved in BL pathogenesis. OBJECTIVE To describe immunoglobulin heavy variable (IgHV) rearrangement and micro-RNA expressions in BL tumours. METHODS Genomic DNA were extracted and purified from BL tissue blocks at Moi Teaching and Referral Hospital, before amplification using IgHV consensus primers and sequencing. The sequences were then aligned with germline alleles in IMGT/V-QUEST® database. Total RNA extracted from tissue blocks and cell lines were used to determine relative expression of hsamiR-34a and hsa-miR-127. RESULTS In all tumours, allele alignment scores and number of mutations range were 89.2-93.2%, 15-24 respectively. The range of IgHV amino acid changes were higher in EBER-1+ (15-25) than EBER-1- (9-15). In MYC+ tumours, the relative expression were: hsa-miR-127(2.09);hsa-miR-34a (2.8) and MYC- hsa-miR-127 (1.2), hsa-miR-34a (1.0). CONCLUSION B-cell in BL contained somatic mutated IgHV gene and upregulated cellular microRNAs with possible pathogenetic role(s).
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Affiliation(s)
- Isaac Ndede
- Department of Immunology, Moi University School of Medicine, Eldoret, Kenya
- Department of Biological Sciences, University of Eldoret, Eldoret, Kenya
| | - SK Mining
- Department of Immunology, Moi University School of Medicine, Eldoret, Kenya
| | - K Patel
- Department of Immunology, Moi University School of Medicine, Eldoret, Kenya
| | - FM Wanjala
- Department of Biological Sciences, University of Eldoret, Eldoret, Kenya
| | - C Tenge
- Department of Child Health and Paediatrics, Moi University School of Medicine, Eldoret, Kenya
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21
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Molecular switch from MYC to MYCN expression in MYC protein negative Burkitt lymphoma cases. Blood Cancer J 2019; 9:91. [PMID: 31748534 PMCID: PMC6868231 DOI: 10.1038/s41408-019-0252-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 07/29/2019] [Accepted: 08/19/2019] [Indexed: 12/21/2022] Open
Abstract
MYC is the most altered oncogene in human cancer, and belongs to a large family of genes, including MYCN and MYCL. Recently, while assessing the degree of correlation between MYC gene rearrangement and MYC protein expression in aggressive B-cell lymphomas, we observed few Burkitt lymphoma (BL) cases lacking MYC protein expression despite the translocation involving the MYC gene. Therefore, in the present study we aimed to better characterize such cases. Our results identified two sub-groups of MYC protein negative BL: one lacking detectable MYC protein expression but presenting MYCN mRNA and protein expression; the second characterized by the lack of both MYC and MYCN proteins but showing MYC mRNA. Interestingly, the two sub-groups presented a different pattern of SNVs affecting MYC gene family members that may induce the switch from MYC to MYCN. Particulary, MYCN-expressing cases show MYCN SNVs at interaction interface that stabilize the protein associated with loss-of-function of MYC. This finding highlights MYCN as a reliable diagnostic marker in such cases. Nevertheless, due to the overlapping clinic, morphology and immunohistochemistry (apart for MYC versus MYCN protein expression) of both sub-groups, the described cases represent bona fide BL according to the current criteria of the World Health Organization.
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22
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Wagener R, Bens S, Toprak UH, Seufert J, López C, Scholz I, Herbrueggen H, Oschlies I, Stilgenbauer S, Schlesner M, Klapper W, Burkhardt B, Siebert R. Cryptic insertion of MYC exons 2 and 3 into the immunoglobulin heavy chain locus detected by whole genome sequencing in a case of " MYC-negative" Burkitt lymphoma. Haematologica 2019; 105:e202-e205. [PMID: 31073073 DOI: 10.3324/haematol.2018.208140] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Affiliation(s)
- Rabea Wagener
- Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm
| | - Susanne Bens
- Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm
| | - Umut H Toprak
- German Cancer Research Center (DKFZ), Bioinformatics and Omics Data Analytics, Heidelberg.,German Caner Research Center (DKFZ), Division of Neuroblastoma Genomics Heidelberg.,Faculty of Biosciences, Heidelberg University, Heidelberg
| | - Julian Seufert
- German Cancer Research Center (DKFZ), Bioinformatics and Omics Data Analytics, Heidelberg.,Faculty of Biosciences, Heidelberg University, Heidelberg
| | - Cristina López
- Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm
| | - Ingrid Scholz
- Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg
| | - Heidi Herbrueggen
- Department of Pediatric Hematology and Oncology, NHL-BFM Study Center, University Children's Hospital, Münster
| | - Ilske Oschlies
- Hematopathology Section, Christian-Albrechts University, Kiel
| | | | - Matthias Schlesner
- German Cancer Research Center (DKFZ), Bioinformatics and Omics Data Analytics, Heidelberg
| | - Wolfram Klapper
- Hematopathology Section, Christian-Albrechts University, Kiel
| | - Birgit Burkhardt
- Department of Pediatric Hematology and Oncology, NHL-BFM Study Center, University Children's Hospital, Münster
| | - Reiner Siebert
- Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm
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23
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Liao H, Liao M, Xu L, Yan X, Ren B, Zhu Z, Yuan K, Zeng Y. Integrative analysis of h-prune as a potential therapeutic target for hepatocellular carcinoma. EBioMedicine 2019; 41:310-319. [PMID: 30665854 PMCID: PMC6444224 DOI: 10.1016/j.ebiom.2019.01.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Revised: 12/26/2018] [Accepted: 01/03/2019] [Indexed: 02/05/2023] Open
Abstract
Background Drosophila prune protein (h-prune) has been proved to play an essential role in regulating tumor metastasis. However, the clinical relevance of h-prune and its potential mechanism in regulating hepatocellular carcinoma (HCC) are still poorly understood. Methods In this study, we used tissue microarrays (TMA) containing 304 HCC tumor samples to evaluate the expression of h-prune and its correlation with prognosis. Data of RNAseq, mutation profiles, copy number variation (CNV), miRNAseq and methylation array from The Cancer Genome Atlas (TCGA) dataset were adopted to analyze the distinctive genomic patterns associated with h-prune expression. Results By using TMA, we found increased expression of h-prune in HCC tumor cells compared with adjacent normal tissues. Higher expression of h-prune was correlated with poorer OS and DFS outcomes. In addition, multivariate analysis showed that h-prune expression was an independent risk factor for both OS and DFS. Gene enrichment analysis showed that the gene signatures of cell proliferation, DNA methylation and canonical Wnt signaling pathway were enriched in h-prune-high patients. Notably, somatic mutation analysis demonstrated that higher mutation burden of RB1 and RPS6KA3 could be observed in h-prune-high patients. Moreover, integrative analysis revealed a strong correlation between h-prune expression and epigenetic changes. Interpretation This study has highlighted the clinical value of h-prune in predicting the prognosis of HCC patients and its essential role in promoting tumorigenesis of HCC.
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Affiliation(s)
- Haotian Liao
- Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Mingheng Liao
- Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Lin Xu
- Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Xiaokai Yan
- Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Bo Ren
- Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Zexin Zhu
- Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Kefei Yuan
- Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China; Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.
| | - Yong Zeng
- Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China; Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.
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Zhang Y, Wang H, Ren C, Yu H, Fang W, Zhang N, Gao S, Hou Q. Correlation Between C-MYC, BCL-2, and BCL-6 Protein Expression and Gene Translocation as Biomarkers in Diagnosis and Prognosis of Diffuse Large B-cell Lymphoma. Front Pharmacol 2019; 9:1497. [PMID: 30666200 PMCID: PMC6330311 DOI: 10.3389/fphar.2018.01497] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Accepted: 12/07/2018] [Indexed: 12/22/2022] Open
Abstract
This study investigates the protein expression of C-MYC, BCL-2, and BCL-6 in diffuse large B-cell lymphoma (DLBCL) and their relationship with genetic abnormalities. A retrospective study of 42 cases on paraffin-embedded tissue specimens diagnosed with DLBCL was performed using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). The expression of C-MYC, BCL-2, BCL-6 protein, and gene abnormalities in these tissue samples was analyzed. The relationship in genetic abnormalities and Ki-67, Hans classification, gender, and age was also evaluated. It was found that the positive rate of C-MYC expression was 47.6% (20/42), the rate of C-MYC gene abnormality was 26.2% (11/42), in which gene translocation accounted for 23.8% (10/42) and gene amplification 2.4% (1/42); C-MYC protein expression was positively correlated with C-MYC gene translocation (χ2 = 11.813; P = 0.001); C-MYC gene translocation was mainly found in germinal center B cell type (χ2 = 4.029; P = 0.045). The positive rate of BCL-2 protein expression was 85.71% (36/42), the positive rate of translocation was 42.86% (18/42) and the amplification rate was 26.19% (11/42); the overexpression of BCL-2 protein was correlated with the BCL-2 translocation (χ2 = 3.407; P = 0.029). The positive rate of BCL-6 protein expression was 45.24% (19/42), the positive rate of BCL-6 translocation was 14.29% (6/42) and the positive rate of BCL-6 amplification was 7.14% (3/42); the overexpression of BCL-6 protein was significantly correlated with BCL-6 translocation (χ2 = 6.091; P = 0.014). The Ki-67 index was significantly higher in C-MYC translocation cases than in non-C-MYC translocation cases (χ2 = 4.492; P = 0.034). Taken together, our results suggest that the protein expression of C-MYC, BCL-2, and BCL-6 are positively correlated with their gene translocation. Overexpression of C-MYC, BCL-2, BCL-6 protein suggests the possibility of translocation. Therefore, immunohistochemical detection of C-MYC, BCL-2, and BCL-6 are useful in diagnosis and prognosis of DLBCL.
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Affiliation(s)
- YunXiang Zhang
- Department of Pathology, Weifang People's Hospital, Weifang, China
| | - Hui Wang
- Department of Pathology, Weifang People's Hospital, Weifang, China
| | - Cuiai Ren
- Department of Pathology, Weifang People's Hospital, Weifang, China
| | - Hai Yu
- Department of Pathology, Werfang Traditional Chinese Hospital, Weifang, China
| | - Wenjia Fang
- Department of Clinical Medicine, Nanchang University Medical College, Nanchang, China
| | - Na Zhang
- Department of Pathology, Weifang People's Hospital, Weifang, China
| | - Sumei Gao
- Department of Pathology, Weifang People's Hospital, Weifang, China
| | - Qian Hou
- Department of Pathology, Weifang People's Hospital, Weifang, China
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New MYC IHC Classifier Integrating Quantitative Architecture Parameters to Predict MYC Gene Translocation in Diffuse Large B-Cell Lymphoma. Appl Immunohistochem Mol Morphol 2018; 26:54-63. [PMID: 27093450 PMCID: PMC5753811 DOI: 10.1097/pai.0000000000000367] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
A new automated MYC IHC classifier based on bivariate logistic regression is presented. The predictor relies on image analysis developed with the open-source ImageJ platform. From a histologic section immunostained for MYC protein, 2 dimensionless quantitative variables are extracted: (a) relative distance between nuclei positive for MYC IHC based on euclidean minimum spanning tree graph and (b) coefficient of variation of the MYC IHC stain intensity among MYC IHC-positive nuclei. Distance between positive nuclei is suggested to inversely correlate MYC gene rearrangement status, whereas coefficient of variation is suggested to inversely correlate physiological regulation of MYC protein expression. The bivariate classifier was compared with 2 other MYC IHC classifiers (based on percentage of MYC IHC positive nuclei), all tested on 113 lymphomas including mostly diffuse large B-cell lymphomas with known MYC fluorescent in situ hybridization (FISH) status. The bivariate classifier strongly outperformed the “percentage of MYC IHC-positive nuclei” methods to predict MYC+ FISH status with 100% sensitivity (95% confidence interval, 94-100) associated with 80% specificity. The test is rapidly performed and might at a minimum provide primary IHC screening for MYC gene rearrangement status in diffuse large B-cell lymphomas. Furthermore, as this bivariate classifier actually predicts “permanent overexpressed MYC protein status,” it might identify nontranslocation-related chromosomal anomalies missed by FISH.
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26
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Rosenthal A, Rimsza L. Genomics of aggressive B-cell lymphoma. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2018; 2018:69-74. [PMID: 30504293 PMCID: PMC6245962 DOI: 10.1182/asheducation-2018.1.69] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/11/2023]
Abstract
The growing body of genomic information collected and applied to mature aggressive B-cell lymphoma diagnosis and management has exploded over the last few years due to improved technologies with high-throughput capacity, suitable for use on routine formalin-fixed, paraffin-embedded tissue biopsies, and decreasing costs. These techniques have made evaluation of complete DNA sequences, RNA-expression patterns, translocations, copy-number alterations, loss of heterozygosity, and DNA-methylation patterns possible on a genome-wide level. This chapter will present a case of aggressive B-cell lymphoma and discuss the most important genomic abnormalities that characterize this group of entities in the recent update to the fourth edition of the World Health Organization (WHO) lymphoma classification system. Genomic abnormalities discussed will include those necessary for certain diagnoses such as translocations of MYC, BCL2, or BCL6; gene-expression-profiling categorization; the newly defined Burkitt-like lymphoma with 11q abnormalities; prognostic and predictive mutations, as well as tumor heterogeneity. Finally, our current practices for clinical triage of specimens with a potential diagnosis of aggressive B-cell lymphomas are also described. Options for treatment at relapse, in light of these genomic features, will be discussed in the third presentation from this session.
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Affiliation(s)
- Allison Rosenthal
- Division of Hematology Medical Oncology, Division of Internal Medicine, Mayo Clinic Arizona, Phoenix, AZ; and
| | - Lisa Rimsza
- Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Phoenix, AZ
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27
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Solé C, Arnaiz E, Lawrie CH. MicroRNAs as Biomarkers of B-cell Lymphoma. Biomark Insights 2018; 13:1177271918806840. [PMID: 30349178 PMCID: PMC6195009 DOI: 10.1177/1177271918806840] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Accepted: 09/20/2018] [Indexed: 12/13/2022] Open
Abstract
B-cell lymphomas represent a diverse group of neoplasms classified primarily by histopatholgy and are often challenging to accurately diagnose. Despite having been recognized less than 20 years ago, microRNAs (miRNAs) have emerged as one of the most promising class of cancer molecular biomarkers and are particularly attractive as they can be readily detected in formalin-fixed paraffin-embedded biopsy material and biological fluids such as blood. Many of the identified B-cell lymphoma miRNA biomarkers also play crucial regulatory roles in normal B-cell development. Below we consider the identity, function, and biomarker potential of miRNAs in B-cell lymphoma and most importantly the barriers that remain to be overcome if they are really to become part of routine clinical practice.
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Affiliation(s)
- Carla Solé
- Molecular Oncology Group, Biodonostia Research Institute, San Sebastián, Spain
| | - Esther Arnaiz
- Molecular Oncology Group, Biodonostia Research Institute, San Sebastián, Spain
| | - Charles H Lawrie
- Molecular Oncology Group, Biodonostia Research Institute, San Sebastián, Spain.,Nuffield Division of Clinical Laboratory Sciences, University of Oxford, Oxford, UK.,Ikerbasque, Basque Foundation for Science, Bilbao, Spain
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28
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Alayed K, Schweitzer K, Awadallah A, Shetty S, Turakhia S, Meyerson H. A multicolour flow cytometric assay for c-MYC protein in B-cell lymphoma. J Clin Pathol 2018; 71:906-915. [PMID: 29769234 DOI: 10.1136/jclinpath-2018-205075] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2018] [Revised: 04/20/2018] [Accepted: 04/30/2018] [Indexed: 11/03/2022]
Abstract
AIM Develop an objective assay to detect c-MYC protein expression using multiparametric flow cytometry (FCM) as an alternative to immunohistochemistry (IHC). METHODS 57 patient samples and 11 cell line samples were evaluated. Cell suspensions were obtained and c-MYC staining was performed in combination with CD45 and CD19 and, in some samples, CD10. The percentage of c-MYC+ cells by FCM was correlated with the percentage determined by IHC. The relationship between c-MYC protein expression and the presence of a c-MYC gene rearrangement in aggressive and high-grade lymphomas was also assessed. RESULTS c-MYC expression by FCM and IHC demonstrated a high degree of correlation in a training set of 33 patient cases, r=0.92, 11 cell line samples, r=0.81 and in a validation set of 24 aggressive and high-grade B-cell lymphomas, r=0.85. c-MYC gene was rearranged by fluorescence in situ hybridisation in 6/9 samples with high c-MYC expression (>40%) by FCM and 6/14 by IHC. CONCLUSIONS We have developed a reliable multicolour FCM assay to detect c-MYC expression suitable for clinical laboratories that should be helpful to accurately quantify c-MYC expression in B-cell lymphomas.
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Affiliation(s)
- Khaled Alayed
- Department of Pathology, University Hospitals Cleveland Medical Center and Seidman Comprehensive Cancer Center, Cleveland, Ohio, USA.,Department of Pathology, King Saud University, Riyadh, Saudi Arabia
| | - Karen Schweitzer
- Department of Pathology, University Hospitals Cleveland Medical Center and Seidman Comprehensive Cancer Center, Cleveland, Ohio, USA
| | - Amad Awadallah
- Department of Pathology, University Hospitals Cleveland Medical Center and Seidman Comprehensive Cancer Center, Cleveland, Ohio, USA
| | - Shashirekha Shetty
- Department of Pathology, University Hospitals Cleveland Medical Center and Seidman Comprehensive Cancer Center, Cleveland, Ohio, USA
| | - Samir Turakhia
- Department of Pathology, University Hospitals Cleveland Medical Center and Seidman Comprehensive Cancer Center, Cleveland, Ohio, USA
| | - Howard Meyerson
- Department of Pathology, University Hospitals Cleveland Medical Center and Seidman Comprehensive Cancer Center, Cleveland, Ohio, USA
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Panatta E, Lena AM, Mancini M, Affinati M, Smirnov A, Annicchiarico-Petruzzelli M, Piro MC, Campione E, Bianchi L, Mazzanti C, Melino G, Candi E. Kruppel-like factor 4 regulates keratinocyte senescence. Biochem Biophys Res Commun 2018; 499:389-395. [DOI: 10.1016/j.bbrc.2018.03.172] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Accepted: 03/22/2018] [Indexed: 01/07/2023]
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30
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Prognostic significances of overexpression MYC and/or BCL2 in R-CHOP-treated diffuse large B-cell lymphoma: A Systematic review and meta-analysis. Sci Rep 2018; 8:6267. [PMID: 29674626 PMCID: PMC5908914 DOI: 10.1038/s41598-018-24631-5] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Accepted: 04/05/2018] [Indexed: 12/31/2022] Open
Abstract
Numerous studies have investigated the prognostic values of MYC and/or BCL2 protein overexpression in diffuse large B-cell lymphoma (DLBCL). However, the results still demonstrate discrepancies among different studies. We aimed to do a systematic review and meta-analysis on the relationships between overexpression MYC and/or BCL2 and DLBCLs treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). This study followed the guidelines of PRISMA and Cochrane handbook. The hazard ratios (HRs) for overall survival (OS) were pooled to estimate the main effect size. Twenty studies recruited a total of 5576 patients were available for this meta-analysis. The results showed that MYC (HR = 1.96, 95%CI (confidence interval) = 1.69–2.27)without heterogeneity(I2 = 17.2%, P = 0.280), BCL2 (HR = 1.65, 95%CI = 1.43–1.89, I2 = 20.7%, P = 0.234) protein overexpression, and co-overexpression (HR = 2.58, 95%CI = 2.19–3.04, I2 = 17.2%, P = 0.275) had a poor prognosis in R-CHOP treated DLBCL patients, respectively. The current analysis indicated that MYC and/or BCL2 protein overexpression, and particularly co-overexpression was related to short overall survival in R-CHOP treated DLBCL patients, showing that application of the two new biomarkers can help to better stratify DLBCL patients and guide targeted treatment.
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31
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Abstract
The contribution of Epstein-Barr virus (EBV) to the development of specific types of benign lymphoproliferations and malignant lymphomas has been extensively studied since the discovery of the virus over the last 50 years. The importance and better understanding of the EBV-associated lymphoproliferative disorders (LPD) of B, T or natural killer (NK) cell type has resulted in the recognition of new entities like EBV+ mucocutaneous ulcer or the addition of chronic active EBV (CAEBV) infection in the revised 2016 World Health Organization (WHO) lymphoma classification. In this article, we review the definitions, morphology, pathogenesis, and evolving concepts of the various EBV-associated disorders including EBV+ diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), EBV+ mucocutaneous ulcer, DLBCL associated with chronic inflammation, fibrin-associated DLBCL, lymphomatoid granulomatosis, the EBV+ T and NK-cell LPD of childhood, aggressive NK leukaemia, extranodal NK/T-cell lymphoma, nasal type, and the new provisional entity of primary EBV+ nodal T- or NK-cell lymphoma. The current knowledge regarding the pathogenesis of B-cell lymphomas that can be EBV-associated including Burkitt lymphoma, plasmablastic lymphoma and classic Hodgkin lymphoma will be also explored.
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32
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Ding Y, Wang ZC, Zheng Y, Hu Z, Li Y, Luo DF, Wang SY. C-Myc functions as a competing endogenous RNA in acute promyelocytic leukemia. Oncotarget 2018; 7:56422-56430. [PMID: 27486764 PMCID: PMC5302924 DOI: 10.18632/oncotarget.10896] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 07/09/2016] [Indexed: 11/25/2022] Open
Abstract
Recent reports have described a new post-transcriptional regulation that RNA transcripts can crosstalk with each other by competing for their common microRNAs. These RNA transcripts termed competing endogenous RNAs (ceRNAs) regulate the distribution of miRNAs on their targets. One corollary from ceRNA interaction is that chromosomal translocation in acute promyelocytic leukemia (APL) would perturb ceRNA regulation due to altered expression of 3'UTRs. In our study, we demonstrate that expression of PML/RARα, the APL-associated fusion oncogene is repressed by c-Myc mRNA transcript independent of protein-coding function but dependent upon microRNA. Attenuation of c-Myc transcript results in PML/RARα-degraded cellular phenotypes in APL cells, but these Myc reduction-associated cell phenotypes are sufficient to abrogate in a microRNA dependent manner. We also show that let-7 microRNA family members promote differentiation of All-Trans-Retinoic Acid (ATRA)-induced NB4 cells and their activities are affected by expression levels of both c-Myc and PML/RARα through altering miRNA targets. These results indicate that c-Myc mRNA represses PML/RARα expression via altering the distribution of let-7 miRNAs on their targets. Our findings reveal a previously unrecognized role of c-Myc as a potential ceRNA for PML/RARα in APL.
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Affiliation(s)
- Ye Ding
- Union Clinical Medical College, Fujian Medical University, Fuzhou, P.R. China
| | - Ze-Chuan Wang
- Union Clinical Medical College, Fujian Medical University, Fuzhou, P.R. China
| | - Yi Zheng
- Union Clinical Medical College, Fujian Medical University, Fuzhou, P.R. China
| | - Zheng Hu
- Union Clinical Medical College, Fujian Medical University, Fuzhou, P.R. China
| | - Yang Li
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, Fuzhou, P.R. China
| | - Dong-Feng Luo
- Union Clinical Medical College, Fujian Medical University, Fuzhou, P.R. China
| | - Shao-Yuan Wang
- Union Clinical Medical College, Fujian Medical University, Fuzhou, P.R. China.,Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, Fuzhou, P.R. China
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33
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34
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De Souza MT, Vera-Lozada G, Othman M, Marques-Salles TJ, Pinto LW, da Rocha MM, Rouxinol S, Liehr T, Ribeiro RC, Hassan R, Silva MLM. Molecular and Cytogenetic Studies in a Child with Burkitt Lymphoma and Ataxia-Telangiectasia Syndrome Harboring MYC Overexpression and Partial Trisomy 8. Ann Lab Med 2017; 38:63-66. [PMID: 29071822 PMCID: PMC5700150 DOI: 10.3343/alm.2018.38.1.63] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Revised: 06/28/2017] [Accepted: 09/11/2017] [Indexed: 11/19/2022] Open
Affiliation(s)
- Mariana T De Souza
- Cytogenetics Department, Bone Marrow Transplantation Center, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brazil.,Post Graduation Oncology Program, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brazil
| | - Gabriela Vera-Lozada
- Post Graduation Oncology Program, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brazil.,Oncovirology Laboratory, Bone Marrow Transplantation Center, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brazil
| | - Moneeb Othman
- Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Jena, TH, Germany
| | | | - Luciana W Pinto
- Integrated Department of Pathology, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brazil
| | - Moisés M da Rocha
- Cytogenetics Department, Bone Marrow Transplantation Center, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brazil
| | - Soraia Rouxinol
- Pediatric Hematology Department, Hospital Federal da Lagoa, Rio de Janeiro, RJ, Brazil
| | - Thomas Liehr
- Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Jena, TH, Germany
| | - Raul C Ribeiro
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.,Instituto Pelé Pequeno Príncipe, Postgraduate Program in Child Adolescent Health, Curitiba, Paraná, Brazil
| | - Rocio Hassan
- Post Graduation Oncology Program, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brazil.,Oncovirology Laboratory, Bone Marrow Transplantation Center, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brazil
| | - Maria Luiza M Silva
- Cytogenetics Department, Bone Marrow Transplantation Center, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brazil.,Post Graduation Oncology Program, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brazil.
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Solé C, Larrea E, Di Pinto G, Tellaetxe M, Lawrie CH. miRNAs in B-cell lymphoma: Molecular mechanisms and biomarker potential. Cancer Lett 2017; 405:79-89. [DOI: 10.1016/j.canlet.2017.07.020] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Revised: 07/06/2017] [Accepted: 07/14/2017] [Indexed: 12/16/2022]
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36
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Ott G. Aggressive B-cell lymphomas in the update of the 4th edition of the World Health Organization classification of haematopoietic and lymphatic tissues: refinements of the classification, new entities and genetic findings. Br J Haematol 2017; 178:871-887. [PMID: 28748558 DOI: 10.1111/bjh.14744] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The update of the 4th edition of the World Health Organization Classification of Haematopoietic and Lymphatic Tissues portends important new findings and concepts in the diagnosis, classification and biology of lymphomas. This review summarizes the basic concepts and cornerstones of the classification of aggressive B-cell lymphomas and details the major changes. Of importance, there is a new concept of High-grade B-cell lymphomas (HGBL), partly replacing the provisional entity of B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma, the so-called grey zone lymphomas. They either harbour MYC translocations together with a BCL2 and/or a BCL6 rearrangement (HGBL-Double Hit) or HGBL, not otherwise specified (NOS), lacking a double or triple hit constellation. In addition, the requirement for providing the cell-of-origin classification in the diagnostic work-up of DLBCLs, the role of MYC alterations in DLBCL subtypes, and newer findings in the specific variants/subtypes are highlighted.
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Affiliation(s)
- German Ott
- Department of Clinical Pathology, Robert-Bosch-Krankenhaus, Stuttgart, Germany
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37
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Broecker-Preuss M, Becher-Boveleth N, Bockisch A, Dührsen U, Müller S. Regulation of glucose uptake in lymphoma cell lines by c-MYC- and PI3K-dependent signaling pathways and impact of glycolytic pathways on cell viability. J Transl Med 2017; 15:158. [PMID: 28724379 PMCID: PMC5517804 DOI: 10.1186/s12967-017-1258-9] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Accepted: 07/04/2017] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Changes in glucose and energy metabolism contribute to the altered phenotype of cancer cells and are the basis for positron emission tomography with 18F-fluoro-2-deoxy-D-glucose (FDG) to visualize tumors in vivo. The molecular background of the enhanced glucose uptake and its regulation in lymphoma cells is not fully clarified and may provide new possibilities to reverse the altered metabolism. Thus in this study we investigated regulation of glucose uptake by different signaling pathways. Furthermore, the effect of the glucose analog 2-deoxy-D-glucose (2-DG) alone and in combination with other inhibitors on cell survival was studied. METHODS An FDG uptake assay was established and uptake of FDG by lymphoma cells was determined after incubation with inhibitors of the c-MYC and the PI3K signalling pathways that are known to be activated in lymphoma cells and able to regulate glucose metabolism. Inhibitors of MAPK signalling pathways whose role in altered metabolism is still unclear were also investigated. Expression of mRNAs of the glucose transporter 1 (GLUT1), hexokinase 2 (HK2), glucose-6-phosphatase (G6Pase) and lactate dehydrogenase A (LDHA) and of the glucose metabolism-regulating micro RNAs (miRNA) miR21, -23a, -133a, -133b, -138-1 and -143 was determined by RT-PCR. Cell viability was analysed by MTT assay. RESULTS Treatment with the c-MYC inhibitor 10058-F4 and inhibitors of the PI3K/mTOR pathway diminished uptake of FDG in all three cell lines, while inhibition of MAPK pathways had no effect on glucose uptake. Expression of glycolysis-related genes and miRNAs were diminished, although to a variable degree in the three cell lines. The c-MYC inhibitor, the PI3K inhibitor LY294002, the mTOR inhibitor Rapamycin and 2-DG all diminished the number of viable cells. Interestingly, in combination with 2-DG, the c-MYC inhibitor, LY294002 and the p38 MAPK inhibitor SB203580 had synergistic effects on cell viability in all three cell lines. CONCLUSIONS c-MYC- and PI3K/mTOR-inhibitors decreased viability of the lymphoma cells and led to decreased glucose uptake, expression of glycolysis-associated genes, and glucose metabolism-regulating miRNAs. Inhibition of HK by 2-DG reduced cell numbers as a single agent and synergistically with inhibitors of other intracellular pathways. Thus, targeted inhibition of the pathways investigated here could be a strategy to suppress the glycolytic phenotype of lymphoma cells and reduce proliferation.
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Affiliation(s)
- Martina Broecker-Preuss
- Department of Nuclear Medicine, University Hospital Essen, Hufelandstr. 55, 45122, Essen, Germany. .,Department of Clinical Chemistry, University Hospital Essen, Hufelandstr. 55, 45122, Essen, Germany.
| | - Nina Becher-Boveleth
- Department of Nuclear Medicine, University Hospital Essen, Hufelandstr. 55, 45122, Essen, Germany.,Department of Hematology, University Hospital Essen, Hufelandstr. 55, 45122, Essen, Germany.,Institute of Pathology, University Hospital Essen, Hufelandstr. 55, 45122, Essen, Germany
| | - Andreas Bockisch
- Department of Nuclear Medicine, University Hospital Essen, Hufelandstr. 55, 45122, Essen, Germany
| | - Ulrich Dührsen
- Department of Hematology, University Hospital Essen, Hufelandstr. 55, 45122, Essen, Germany
| | - Stefan Müller
- Department of Nuclear Medicine, University Hospital Essen, Hufelandstr. 55, 45122, Essen, Germany
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Chisholm KM, Krishnan C, Heerema-McKenney A, Natkunam Y. Immunohistochemical Profile of MYC Protein in Pediatric Small Round Blue Cell Tumors. Pediatr Dev Pathol 2017; 20:213-223. [PMID: 28521631 DOI: 10.1177/1093526616689642] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Deregulation of MYC oncoprotein in cancers can result from multiple oncogenic mechanisms. Although MYC translocations define Burkitt lymphoma and MYC protein expression is a poor prognostic factor in undifferentiated neuroblastomas, the distribution of MYC protein (c-MYC) across other pediatric small round blue cell tumors (SRBCT) has not been well characterized. We undertook this study to assess MYC protein expression in a large cohort of pediatric lymphomas, sarcomas, and other SRBCT. Tissue microarrays containing 302 SRBCT were successfully evaluated by immunohistochemistry using anti-MYC clone Y69, with nuclear positivity scored as 0%, 1%-25%, 26%-50%, 51%-75%, or 76%-100%. MYC protein staining of >50% of lesional cells was identified in 60% of Burkitt lymphomas, 50% of B lymphoblastic lymphomas, 33% of T lymphoblastic lymphomas, 31% of rhabdomyosarcomas, 33% of Ewing sarcomas, and 25% of soft tissue sarcomas, not otherwise specified. Only 14% of neuroblastomas showed >50% staining, and of these, if known, MYCN was not amplified. No cases of Wilms tumor, synovial sarcoma, or desmoplastic small round cell tumor had >50% staining. Recurrences and metastases often had the same percentage of MYC staining (15/30). In conclusion, MYC protein exhibited variable expression across and within pediatric SRBCT subtypes. Overall, these findings provide a baseline for MYC expression in pediatric SRBCT and suggest that there may be multiple mechanisms of MYC upregulation in these different neoplasms.
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Affiliation(s)
- Karen M Chisholm
- 1 Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.,2 Now at Seattle Children's Hospital, Department of Laboratories, Seattle, Washington, USA
| | - Chandra Krishnan
- 3 Dell Children's Medical Center, Department of Pathology, Austin, Texas, USA
| | - Amy Heerema-McKenney
- 4 Pathology and Laboratory Medicine Institute, Cleveland Clinic Cleveland, Ohio, USA
| | - Yasodha Natkunam
- 1 Department of Pathology, Stanford University School of Medicine, Stanford, California, USA
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39
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Role of MYC in B Cell Lymphomagenesis. Genes (Basel) 2017; 8:genes8040115. [PMID: 28375188 PMCID: PMC5406862 DOI: 10.3390/genes8040115] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Revised: 03/20/2017] [Accepted: 03/28/2017] [Indexed: 12/17/2022] Open
Abstract
B cell lymphomas mainly arise from different developmental stages of B cells in germinal centers of secondary lymphoid tissue. There are a number of signaling pathways that affect the initiation and development of B cell lymphomagenesis. The functions of several key proteins that represent branching points of signaling networks are changed because of their aberrant expression, degradation, and/or accumulation, and those events determine the fate of the affected B cells. One of the most influential transcription factors, commonly associated with unfavorable prognosis for patients with B cell lymphoma, is nuclear phosphoprotein MYC. During B cell lymphomagenesis, oncogenic MYC variant is deregulated through various mechanisms, such as gene translocation, gene amplification, and epigenetic deregulation of its expression. Owing to alterations of downstream signaling cascades, MYC-overexpressing neoplastic B cells proliferate rapidly, avoid apoptosis, and become unresponsive to most conventional treatments. This review will summarize the roles of MYC in B cell development and oncogenesis, as well as its significance for current B cell lymphoma classification. We compared communication networks within transformed B cells in different lymphomas affected by overexpressed MYC and conducted a meta-analysis concerning the association of MYC with tumor prognosis in different patient populations.
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Low LK, Song JY. B-cell Lymphoproliferative Disorders Associated with Primary and Acquired Immunodeficiency. Surg Pathol Clin 2016; 9:55-77. [PMID: 26940268 DOI: 10.1016/j.path.2015.10.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The diagnosis of lymphoproliferative disorders associated with immunodeficiency can be challenging because many of these conditions have overlapping clinical and pathologic features and share similarities with their counterparts in the immunocompetent setting. There are subtle but important differences between these conditions that are important to recognize for prognostic and therapeutic purposes. This article provides a clinicopathologic update on how understanding of these B-cell lymphoproliferations in immunodeficiency has evolved over the past decade.
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Affiliation(s)
- Lawrence K Low
- Department of Pathology, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA
| | - Joo Y Song
- Department of Pathology, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA.
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41
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Herviou L, Cavalli G, Cartron G, Klein B, Moreaux J. EZH2 in normal hematopoiesis and hematological malignancies. Oncotarget 2016; 7:2284-96. [PMID: 26497210 PMCID: PMC4823035 DOI: 10.18632/oncotarget.6198] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Accepted: 10/14/2015] [Indexed: 12/20/2022] Open
Abstract
Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the Polycomb repressive complex 2, inhibits gene expression through methylation on lysine 27 of histone H3. EZH2 regulates normal hematopoietic stem cell self-renewal and differentiation. EZH2 also controls normal B cell differentiation. EZH2 deregulation has been described in many cancer types including hematological malignancies. Specific small molecules have been recently developed to exploit the oncogenic addiction of tumor cells to EZH2. Their therapeutic potential is currently under evaluation. This review summarizes the roles of EZH2 in normal and pathologic hematological processes and recent advances in the development of EZH2 inhibitors for the personalized treatment of patients with hematological malignancies.
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Affiliation(s)
- Laurie Herviou
- Institute of Human Genetics, CNRS UPR1142, Montpellier, France
| | - Giacomo Cavalli
- Institute of Human Genetics, CNRS UPR1142, Montpellier, France
| | - Guillaume Cartron
- University of Montpellier 1, UFR de Médecine, Montpellier, France.,Department of Clinical Hematology, CHU Montpellier, Montpellier, France
| | - Bernard Klein
- Department of Biological Hematology, CHU Montpellier, Montpellier, France.,Institute of Human Genetics, CNRS UPR1142, Montpellier, France.,University of Montpellier 1, UFR de Médecine, Montpellier, France
| | - Jérôme Moreaux
- Department of Biological Hematology, CHU Montpellier, Montpellier, France.,Institute of Human Genetics, CNRS UPR1142, Montpellier, France.,University of Montpellier 1, UFR de Médecine, Montpellier, France
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42
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Zhang WF, Xiong YW, Zhu TT, Xiong AZ, Bao HH, Cheng XS. MicroRNA let-7g inhibited hypoxia-induced proliferation of PASMCs via G 0/G 1 cell cycle arrest by targeting c-myc. Life Sci 2016; 170:9-15. [PMID: 27889560 DOI: 10.1016/j.lfs.2016.11.020] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Revised: 11/17/2016] [Accepted: 11/22/2016] [Indexed: 01/06/2023]
Abstract
AIMS Pulmonary hypertension (PH) is a proliferative disorder characterized by enhanced proliferation and suppressed apoptosis of intrapulmonary vascular smooth muscle cells. Recently, network-based bioinformatics have identified let-7 family, a tumor suppressive microRNA, regulate multiple interacting targets relevant to PH. However, the role of let-7 in vascular homeostasis in PH remains unknown. Thus, we wanted to investigate the role of let-7 in hypoxia-induced PASMCs proliferation and the underlying mechanism in hypoxic pulmonary hypertension (HPH). MAIN METHODS The male Sprague-Dawley (SD) rats were exposed to hypoxia (10% O2) for 21days to induce HPH. The expression of let-7 was determined by quantitative real-time polymerase chain reaction (qRT-PCR) and in situ hybridization. Primary rat PASMCs were exposed to hypoxia (3% O2). MTS and EDU were performed to evaluate PASMCs proliferation. The mRNA and protein expression of c-myc, Bmi-1 and p16 were determined by qRT-PCR and Western blotting, respectively. The functions of let-7g on PASMCs proliferation, c-myc, Bmi-1 and p16 expression were assessed by let-7g mimic and inhibitor transfection. KEY FINDINGS Among let-7 family members, only let-7b and let-7g were significantly down-regulated in remodeled pulmonary artery in HPH rats. Furthermore, only let-7g level was decreased in hypoxic PASMCs. Either hypoxia or let-7g inhibitor stimulated proliferation of PASMCs, let-7g mimic inhibited hypoxia-induced PASMCs proliferation. C-myc was the target of let-7g in PASMCs. Transfect of let-7g mimic inhibited hypoxia-induced c-myc, Bmi-1 up-regulation and p16 down-regulation, which ultimately controls cell cycle progression. SIGNIFICANCE Loss of inhibition on c-myc-Bmi-1-p16 signaling pathway by let-7g may lead to PASMCs proliferation and vascular remodeling in HPH.
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Affiliation(s)
- Wei-Fang Zhang
- Department of Pharmacy/Cardiovascular medicine, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - You-Wen Xiong
- Jiangxi Supervision and Inspection Center for Medical Devices, Nanchang 330029, China
| | - Tian-Tian Zhu
- Department of Pharmacology, School of Pharmaceutical Science, Central South University, Changsha 410078, China
| | - Ai-Zhen Xiong
- Department of Pharmacy/Cardiovascular medicine, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Hui-Hui Bao
- Department of Pharmacy/Cardiovascular medicine, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Xiao-Shu Cheng
- Department of Pharmacy/Cardiovascular medicine, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China.
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Morscio J, Tousseyn T. Recent insights in the pathogenesis of post-transplantation lymphoproliferative disorders. World J Transplant 2016; 6:505-516. [PMID: 27683629 PMCID: PMC5036120 DOI: 10.5500/wjt.v6.i3.505] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2016] [Revised: 06/30/2016] [Accepted: 08/18/2016] [Indexed: 02/05/2023] Open
Abstract
Post-transplant lymphoproliferative disorder (PTLD) is an aggressive complication of solid organ and hematopoietic stem cell transplantation that arises in up to 20% of transplant recipients. Infection or reactivation of the Epstein-Barr virus (EBV), a ubiquitous human herpesvirus, in combination with chronic immunosuppression are considered as the main predisposing factors, however insight in PTLD biology is fragmentary. The study of PTLD is complicated by its morphological heterogeneity and the lack of prospective trials, which also impede treatment optimization. Furthermore, the broad spectrum of underlying disorders and the graft type represent important confounding factors. PTLD encompasses different malignant subtypes that resemble histologically similar lymphomas in the general population. Post-transplant diffuse large B-cell lymphoma (PT-DLBCL), Burkitt lymphoma (PT-BL) and plasmablastic lymphoma (PT-PBL) occur most frequently. However, in many studies various EBV+ and EBV- PTLD subtypes are pooled, complicating the interpretation of the results. In this review, studies of the gene expression pattern, the microenvironment and the genetic profile of PT-DLBCL, PT-BL and PT-PBL are summarized to better understand the mechanisms underlying post-transplantation lymphomagenesis. Based on the available findings we propose stratification of PTLD according to the histological subtype and the EBV status to facilitate the interpretation of future studies and the establishment of clinical trials.
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44
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Abdulla M, Laszlo S, Triumf J, Hedström G, Berglund M, Enblad G, Amini RM. A population-based study of cellular markers in R-CHOP treated diffuse large B-cell lymphoma patients. Acta Oncol 2016; 55:1126-1131. [PMID: 27549735 DOI: 10.1080/0284186x.2016.1189093] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
AIM To determine the prognostic significance of co-expression of MYC, BCL-2 and BCL-6 proteins in combination with other biomarkers and clinical characteristics within a population-based cohort of diffuse large B-cell lymphoma (DLBCL) patients uniformly treated with R-CHOP. PATIENTS AND METHODS The immunohistochemical (IHC) expression of CD10, BCL-2, BCL-6, MUM1, MYC, CD5, CD30, Ki-67 and p53 was evaluated in a retrospective, population-based study comprising 188 DLBCL patients treated with R-CHOP and diagnosed in Sweden between 2002 and 2012. RESULTS Patients had a median age at diagnosis of 64 years (26-85 years) with a male:female ratio of 1.4:1. Approximately half (52%) of the patients presented with an International Prognostic Index (IPI) age adjusted (IPIaa) ≥ 2. Median follow-up time was 51 months (range 0.4-158) and the five-year lymphoma-specific survival (LSS) was 76%, five-year overall survival (OS) was 65% and five-year progression-free survival (PFS) was 61%. A high Ki-67 value was found in 59% of patients, while p53 overexpression was detected in 12% of patients and MYC, BCL-2 and BCL-6 expression were detected in 42%, 55% and 74% of patients, respectively. IPIaa ≥2 (p = 0.002), Ki-67 ≥ 70% (p = 0.04) and p53 overexpression ≥50% (p = 0.02) were associated with inferior LSS and OS. Co-expression of both MYC (>40%) and BCL-2 (>70%) proteins was detected in 27% of patients and correlated with a significantly inferior LSS (p = 0.0002), OS (p = 0.009) and PFS (p = 0.03). In addition, triple expression of MYC, BCL-2 and BCL-6, also correlated with a significantly inferior LSS (p = 0.02). CONCLUSION Concurrent expression of MYC and BCL-2 proteins, as detected by IHC, was strongly associated with an inferior survival in DLBCL patients treated with R-CHOP. Other markers affecting survival were triple expression of MYC, BCL-2 and BCL-6, IPIaa, high Ki-67 and p53 overexpression.
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Affiliation(s)
- Maysaa Abdulla
- Department of Immunology, Genetics and Pathology, Unit of Pathology, Uppsala University and Uppsala University Hospital, Uppsala, Sweden
| | - Sofia Laszlo
- Department of Immunology, Genetics and Pathology, Unit of Pathology, Uppsala University and Uppsala University Hospital, Uppsala, Sweden
| | - Johanna Triumf
- Department of Immunology, Genetics and Pathology, Unit of Oncology, Uppsala University and Uppsala University Hospital, Uppsala, Sweden
| | - Gustaf Hedström
- Department of Immunology, Genetics and Pathology, Unit of Oncology, Uppsala University and Uppsala University Hospital, Uppsala, Sweden
| | - Mattias Berglund
- Department of Immunology, Genetics and Pathology, Unit of Oncology, Uppsala University and Uppsala University Hospital, Uppsala, Sweden
- Department of Biosciences and Nutrition, Karolinska Institute, Novum, Huddinge, Sweden
| | - Gunilla Enblad
- Department of Immunology, Genetics and Pathology, Unit of Oncology, Uppsala University and Uppsala University Hospital, Uppsala, Sweden
| | - Rose-Marie Amini
- Department of Immunology, Genetics and Pathology, Unit of Pathology, Uppsala University and Uppsala University Hospital, Uppsala, Sweden
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Hartmann S, Döring C, Agostinelli C, Portscher-Kim SJ, Lonardi S, Lorenzi L, Fuligni F, Martinez D, Mehta J, Borges A, Hackstein H, Kippenberger S, Piccaluga PP, Simonitsch-Klupp I, Cabeçadas J, Campo E, Facchetti F, Pileri SA, Hansmann ML. miRNA expression profiling divides follicular dendritic cell sarcomas into two groups, related to fibroblasts and myopericytomas or Castleman's disease. Eur J Cancer 2016; 64:159-66. [PMID: 27423414 DOI: 10.1016/j.ejca.2016.06.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Revised: 05/23/2016] [Accepted: 06/09/2016] [Indexed: 10/21/2022]
Abstract
Follicular dendritic cell (FDC) sarcomas are rare mesenchymal tumours, which are fatal in 20% of the patients and usually occur in secondary lymphoid organs or extranodal localizations. Due to the rareness of these tumours, only few studies have been conducted on molecular level. In the present study, we performed microRNA (miRNA) profiling of 31 FDC sarcomas and identified two subgroups, one with high miRNA expression and the other group with low miRNA expression levels. The first group showed a strong similarity to fibroblasts and myopericytomas, whereas the second group was more closely related to FDCs from Castleman's disease. Both groups showed important differences compared with myeloid-derived dendritic cells, confirming mesenchymal origin of FDCs and their derived sarcomas. The two FDC sarcoma groups did not differ on morphological grounds, mitotic activity or BRAF mutation status. However, patients of group I presented a tendency to a shorter overall survival and more frequent podoplanin expression by immunohistochemistry. The importance of these newly recognized FDC sarcoma subgroups in terms of clinical behaviour and therapeutic implications should be assessed in a larger cohort in future studies.
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Improvements to the HITS-CLIP protocol eliminate widespread mispriming artifacts. BMC Genomics 2016; 17:338. [PMID: 27150721 PMCID: PMC4858895 DOI: 10.1186/s12864-016-2675-5] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Accepted: 04/28/2016] [Indexed: 01/13/2023] Open
Abstract
Background High-throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP) allows for high resolution, genome-wide mapping of RNA-binding proteins. This methodology is frequently used to validate predicted targets of microRNA binding, as well as direct targets of other RNA-binding proteins. Hence, the accuracy and sensitivity of binding site identification is critical. Results We found that substantial mispriming during reverse transcription results in the overrepresentation of sequences complementary to the primer used for reverse transcription. Up to 45 % of peaks in publicly available HITS-CLIP libraries are attributable to this mispriming artifact, and the majority of libraries have detectable levels of mispriming. We also found that standard techniques for validating microRNA-target interactions fail to differentiate between artifactual peaks and physiologically relevant peaks. Conclusions Here, we present a modification to the HITS-CLIP protocol that effectively eliminates this artifact and improves the sensitivity and complexity of resulting libraries. Electronic supplementary material The online version of this article (doi:10.1186/s12864-016-2675-5) contains supplementary material, which is available to authorized users.
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Targeting oncomiRNAs and mimicking tumor suppressor miRNAs: Νew trends in the development of miRNA therapeutic strategies in oncology (Review). Int J Oncol 2016; 49:5-32. [PMID: 27175518 PMCID: PMC4902075 DOI: 10.3892/ijo.2016.3503] [Citation(s) in RCA: 164] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Accepted: 04/29/2016] [Indexed: 12/16/2022] Open
Abstract
MicroRNA (miRNA or miR) therapeutics in cancer are based on targeting or mimicking miRNAs involved in cancer onset, progression, angiogenesis, epithelial-mesenchymal transition and metastasis. Several studies conclusively have demonstrated that miRNAs are deeply involved in tumor onset and progression, either behaving as tumor-promoting miRNAs (oncomiRNAs and metastamiRNAs) or as tumor suppressor miRNAs. This review focuses on the most promising examples potentially leading to the development of anticancer, miRNA-based therapeutic protocols. The inhibition of miRNA activity can be readily achieved by the use of miRNA inhibitors and oligomers, including RNA, DNA and DNA analogues (miRNA antisense therapy), small molecule inhibitors, miRNA sponges or through miRNA masking. On the contrary, the enhancement of miRNA function (miRNA replacement therapy) can be achieved by the use of modified miRNA mimetics, such as plasmid or lentiviral vectors carrying miRNA sequences. Combination strategies have been recently developed based on the observation that i) the combined administration of different antagomiR molecules induces greater antitumor effects and ii) some anti-miR molecules can sensitize drug-resistant tumor cell lines to therapeutic drugs. In this review, we discuss two additional issues: i) the combination of miRNA replacement therapy with drug administration and ii) the combination of antagomiR and miRNA replacement therapy. One of the solid results emerging from different independent studies is that miRNA replacement therapy can enhance the antitumor effects of the antitumor drugs. The second important conclusion of the reviewed studies is that the combination of anti-miRNA and miRNA replacement strategies may lead to excellent results, in terms of antitumor effects.
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Kamoun A, Idbaih A, Dehais C, Elarouci N, Carpentier C, Letouzé E, Colin C, Mokhtari K, Jouvet A, Uro-Coste E, Martin-Duverneuil N, Sanson M, Delattre JY, Figarella-Branger D, de Reyniès A, Ducray F. Integrated multi-omics analysis of oligodendroglial tumours identifies three subgroups of 1p/19q co-deleted gliomas. Nat Commun 2016; 7:11263. [PMID: 27090007 DOI: 10.1038/ncomms11263] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 03/07/2016] [Indexed: 12/26/2022] Open
Abstract
Oligodendroglial tumours (OT) are a heterogeneous group of gliomas. Three molecular subgroups are currently distinguished on the basis of the IDH mutation and 1p/19q co-deletion. Here we present an integrated analysis of the transcriptome, genome and methylome of 156 OT. Not only does our multi-omics classification match the current classification but also reveals three subgroups within 1p/19q co-deleted tumours, associated with specific expression patterns of nervous system cell types: oligodendrocyte, oligodendrocyte precursor cell (OPC) and neuronal lineage. We confirm the validity of these three subgroups using public datasets. Importantly, the OPC-like group is associated with more aggressive clinical and molecular patterns, including MYC activation. We show that the MYC activation occurs through various alterations, including MYC genomic gain, MAX genomic loss, MYC hypomethylation and microRNA-34b/c down-regulation. In the lower grade glioma TCGA dataset, the OPC-like group is associated with a poorer outcome independently of histological grade. Our study reveals previously unrecognized heterogeneity among 1p/19q co-deleted tumours.
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Affiliation(s)
- Aurélie Kamoun
- Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre Le Cancer, 75013 Paris, France
| | - Ahmed Idbaih
- Université Pierre et Marie Curie Paris 6, Centre de Recherche de l'Institut de Cerveau et de la Moelle Epinière (CRICM), UMR 975, 75013 Paris, France.,INSERM U975, 75013 Paris, France.,CNRS, UMR 7225, 75013 Paris, France.,AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2-Mazarin, 75013 Paris, France
| | - Caroline Dehais
- AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2-Mazarin, 75013 Paris, France
| | - Nabila Elarouci
- Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre Le Cancer, 75013 Paris, France
| | - Catherine Carpentier
- Université Pierre et Marie Curie Paris 6, Centre de Recherche de l'Institut de Cerveau et de la Moelle Epinière (CRICM), UMR 975, 75013 Paris, France.,INSERM U975, 75013 Paris, France.,CNRS, UMR 7225, 75013 Paris, France
| | - Eric Letouzé
- Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre Le Cancer, 75013 Paris, France
| | - Carole Colin
- Université de la Méditerranée, Aix-Marseille, Faculté de Médecine La Timone, CRO2, UMR 911, 13885 Marseille, France
| | - Karima Mokhtari
- Université Pierre et Marie Curie Paris 6, Centre de Recherche de l'Institut de Cerveau et de la Moelle Epinière (CRICM), UMR 975, 75013 Paris, France.,INSERM U975, 75013 Paris, France.,CNRS, UMR 7225, 75013 Paris, France.,AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Laboratoire de Neuropathologie R. Escourolle, 75013 Paris, France
| | - Anne Jouvet
- Département de Pathologie et Neuropathologie, Hôpital Neurologique, Hospices Civils de Lyon, 69374 Lyon, France
| | - Emmanuelle Uro-Coste
- CHU Toulouse, Hôpital de Rangueil, Service d'Anatomie et Cytologie Pathologique, 31400 Toulouse, France
| | | | - Marc Sanson
- Université Pierre et Marie Curie Paris 6, Centre de Recherche de l'Institut de Cerveau et de la Moelle Epinière (CRICM), UMR 975, 75013 Paris, France.,INSERM U975, 75013 Paris, France.,CNRS, UMR 7225, 75013 Paris, France.,AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2-Mazarin, 75013 Paris, France
| | - Jean-Yves Delattre
- Université Pierre et Marie Curie Paris 6, Centre de Recherche de l'Institut de Cerveau et de la Moelle Epinière (CRICM), UMR 975, 75013 Paris, France.,INSERM U975, 75013 Paris, France.,CNRS, UMR 7225, 75013 Paris, France.,AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2-Mazarin, 75013 Paris, France.,Onconeurotek, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France
| | - Dominique Figarella-Branger
- Université de la Méditerranée, Aix-Marseille, Faculté de Médecine La Timone, CRO2, UMR 911, 13885 Marseille, France.,AP-HM, Hôpital de la Timone, Service d'Anatomie Pathologique et de Neuropathologie, 13885 Marseille, France
| | - Aurélien de Reyniès
- Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre Le Cancer, 75013 Paris, France
| | - François Ducray
- Hospices Civils de Lyon, Hôpital Neurologique, Service de Neuro-Oncologie, 69374 Lyon, France.,Department of Cancer Cell Plasticity, Cancer Research Centre of Lyon, INSERM U1052, CNRS UMR5286, 69008 Lyon, France.,Université Claude Bernard Lyon 1, 69000 Lyon, France
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Fernandez-Mercado M, Manterola L, Lawrie CH. MicroRNAs in Lymphoma: Regulatory Role and Biomarker Potential. Curr Genomics 2016; 16:349-58. [PMID: 27047255 PMCID: PMC4763973 DOI: 10.2174/1389202916666150707160147] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Revised: 04/20/2015] [Accepted: 04/22/2015] [Indexed: 12/19/2022] Open
Abstract
Although it is now evident that microRNAs (miRNAs) play a critical regulatory role in many, if not all, pathological and physiological processes, remarkably they have only formally been recognized for less than fifteen years. These endogenously produced short non-coding RNAs have created a new paradigm of gene control and have utility as both novel biomarkers of cancer and as potential therapeutics. In this review we consider the role of miRNAs in lymphoid biology both under physiological (i.e. lymphopoiesis) and malignant (i.e. lymphomagenesis) conditions. In addition to the functional significance of aberrant miRNA expression in lymphomas we discuss their use as novel biomarkers, both as a in situ tumour biomarker and as a non-invasive surrogate for the tumour by testing miRNAs in the blood of patients. Finally we consider the use of these molecules as potential therapeutic agents for lymphoma (and other cancer) patients and discuss some of the hurdles yet to be overcome in order to translate this potential into clinical practice
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Affiliation(s)
| | - Lorea Manterola
- Oncology area, Biodonostia Research Institute, San Sebastián, Spain
| | - Charles H Lawrie
- Oncology area, Biodonostia Research Institute, San Sebastián, Spain; ; Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford, UK;; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
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50
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Cao L, Wang N, Pan J, Hu S, Zhao W, He H, Wang Y, Gu G, Chai Y. Clinical significance of microRNA-34b expression in pediatric acute leukemia. Mol Med Rep 2016; 13:2777-84. [PMID: 26861642 DOI: 10.3892/mmr.2016.4876] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2015] [Accepted: 12/03/2015] [Indexed: 11/06/2022] Open
Abstract
The present study aimed to explore the function of miR‑34b promoter methylation in cell proliferation in children's acute leukemia. Quantitative PCR and methylation‑specific PCR were performed to measure the levels of miR‑34b and its promoter methylation in normal cells, eight leukemia cell lines as well as primary leukemic cells isolated from patients newly diagnosed with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) and mixed lymphocytic lymphoma. miR‑34b levels in leukemia cell lines and primary leukemic cells were significantly lower than those in normal cells. The miR‑34b promoter was found to be methylated in all leukemia cell lines, 24 of 31 ALL patients and 8 of 19 AML patients, but not in the 23 normal controls. miR‑34b expression and methylation of its promoter were not associated with most clinical parameters assessed; however, miR‑34b levels in prednisone‑sensitive ALL were significantly different from those in insensitive ALL. A cell counting kit‑8 assay showed that transfection of miR‑34b mimics into K562 cells inhibited their proliferation. Furthermore, treatment with the demethylating agent 5‑aza‑2‑deoxycytidine significantly enhanced miR‑34b expression levels and decreased the methylation status of its promoter in HL‑60 and K562 cells. In conclusion, the results of the present study indicated that in pediatric leukemia cells and leukemia cell lines, the expression of miR‑34b is inhibited by methylation of its promoter, which impairs the restraining effects of miR‑34b on cell proliferation. It was also indicated that the expression of miR‑34b in ALL patients may affect their response to early treatments.
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Affiliation(s)
- Lan Cao
- Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, Jiangsu 215003, P.R. China
| | - Na Wang
- Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, Jiangsu 215003, P.R. China
| | - Jian Pan
- Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, Jiangsu 215003, P.R. China
| | - Shaoyan Hu
- Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, Jiangsu 215003, P.R. China
| | - Wenli Zhao
- Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, Jiangsu 215003, P.R. China
| | - Hailong He
- Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, Jiangsu 215003, P.R. China
| | - Yi Wang
- Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, Jiangsu 215003, P.R. China
| | - Guixiong Gu
- Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, Jiangsu 215003, P.R. China
| | - Yihuan Chai
- Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, Jiangsu 215003, P.R. China
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