IRF8 and lymphomagenesis

IRF8 和淋巴瘤发生

• 批准号: 9898227
• 负责人: Ricardo C Aguiar
• 金额: --
• 依托单位: SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898227
• 关键词: Address; Adult; Affect; Agreement; Animal Model; Apoptosis; B Cell Proliferation; B cell differentiation; B lymphoid malignancy; B-Cell Development; B-Cell Lymphomas; B-Lymphocytes; BCL2 gene; BCL6 gene; Balkans; Biological; Biology; Biopsy; Blood Cells; CD19 gene; Cell Line; Chemical Exposure; Chromosomal translocation; Clinical; Complex; DNA; Data; Deletion Mutation; Development; Diagnosis; Disease; Early Diagnosis; Ectopic Expression; Emu species; Enhancers; Enzymes; Epigenetic Process; Family; Fostering; Functional disorder; Gene Fusion; Genes; Genetic; Genetic Transcription; Genomics; Goals; Human; IFN consensus sequence binding protein; IGH@ gene cluster; Immune; Immuno-Chemotherapy; Immunoglobulin Somatic Hypermutation; In Vitro; Incidence; Infectious Agent; Interferons; Knowledge; Lesion; Link; Lymphoma; Lymphomagenesis; MLL2 gene; Maintenance; Malignant - descriptor; Malignant Neoplasms; Malignant lymphoid neoplasm; Maps; Massive Parallel Sequencing; Mature B-Lymphocyte; Military Personnel; Modeling; Mus; Mutate; Mutation; Oncogenes; Oncogenic; Other Genetics; PAX5 gene; PRDM1 gene; Pathogenesis; Pathway interactions; Patients; Phenotype; Physiological; Point Mutation; Population; Process; Proteins; Reaction; Reporting; Research; Resistance; Risk; Role; Secondary to; Somatic Mutation; Structure of germinal center of lymph node; Testing; Therapeutic; Transgenic Organisms; Tumor Suppressor Genes; Tumor Suppressor Proteins; Variant; Veterans; Vietnam; Western World; activation-induced cytidine deaminase; cancer type; gain of function; histone methyltransferase; in vivo; large cell Diffuse non-Hodgkin' s lymphoma; member; mouse model; mutant; next generation sequencing; novel; novel marker; plasma cell differentiation; pressure; programs; trait; transcription factor; tumor

The advent of massive parallel sequencing highlighted the genetic complexity of cancer, and unveiled the putative contribution of several unsuspected genes to the process of malignant transformation. These advances also indicated a need for the systematic examination of newly-found mutant genes as to determine whether they truly contribute to cancer pathogenesis, or simply represent innocuous variants irrelevant to the observed phenotype. Diffuse large B cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is curable in only ~60% of cases. This clinical challenge is associated with the disease’s complex genetics, which include disruption of epigenetic modifiers, constitutive activation of the NF-κB pathway, and deregulation of B cell relevant transcription factors. The latter, can derive from chromosomal translocation, genomic amplification/deletions and somatic mutations. Recently, we developed an IGH-targeted capture/sequencing strategy and discovered novel aberrant gene fusions in DLBCL including the juxtaposing of IRF8 (interferon regulatory factor 8) to the IGH locus, t(14;16)(q32;q24), a prototypical model of transcription factor deregulation in B cell lymphomas. Independently, IRF8 was found to be somatically mutated in ~10% of DLBCL biopsies. Interestingly, close to 50% of the IRF8-mutant DLBCLs also have mutations in KMT2D, a histone methyltransferase that when inactivated enhances the lymphomagenic potential of other genetic lesions. IRF8, a member of the interferon family of transcription factors, is expressed in the germinal center (GC) where it directly influences the expression of several key regulators of the GC reaction, including BCL6, AICDA and PRDM1. The central objective of this proposal is to test the hypothesis that IRF8 is a bona fide oncogene in DLBCL, which can be deregulated by chromosomal translocation and somatic mutations. To advance this concept, we found that ectopic expression of IRF8 in DLBCL cell lines promotes a lymphomagenic profile characterized by induction of BCL6 and AICDA, suppression of PRDM1 and resistance to apoptosis. In addition, we generated preliminary data to show that the missense IRF8 mutants found in DLBCL are all gain-of-function. Lastly, we created a mouse with B cell restricted transgenic expression of Irf8. Building on our preliminary data, and on the availability of this novel animal model, we propose to address the following specific aims: 1) Determine the mechanism for Irf8 lymphomagenesis in a mouse model that mimics the IGH/IRF8 fusion found in human DLBCL; 2) Characterize in vivo the pro-lymphoma cooperation between the oncogenic Irf8 and the tumor suppressor Kmt2d; 3) Define the functional consequences of the somatic IRF8 mutations found in DLBCL. When this project is completed, we will show that IRF8 functions as an oncogene that cooperates with KMT2D loss for the development of DLBCL. We also expect to mechanistically link IRF8’s lymphomagenesis to the deregulation of BCL6, AICDA and PRDM1.

大规模平行测序技术的出现凸显了癌症基因的复杂性，并揭开了癌症的神秘面纱