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Identifying/Targeting Mechanisms of Lymphomagenesis Driven by CREBBP Inactivation

CREBBP 失活驱动的淋巴瘤发生的识别/靶向机制

基本信息

批准号：
9514039
负责人：
Michael Richard Green
金额：
$ 34.04万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-04 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9514039
关键词：
Acetylation Antigen Presentation Antigens Automobile Driving B cell differentiation B lymphoid malignancy B-Cell Development B-Lymphocytes BCL2 gene Biological Assay CD4 Positive T Lymphocytes CREBBP gene Cell Line Cell physiology Cells Chromosomal translocation Clustered Regularly Interspaced Short Palindromic Repeats Coculture Techniques Complex Cytotoxic T-Lymphocytes Development Disease Down-Regulation EZH2 gene Epigenetic Process Event Evolution Follicular Lymphoma Frequencies Gene Expression Gene Expression Profile Gene Targeting Genes Genetic Genetic Transcription Genome Histone Acetylation Histone Deacetylase Inhibitor Human Immune Evasion Immunocompetent In Vitro Induced Mutation Isogenic transplantation Lead Lymphoma Lymphomagenesis MHC Class II Genes MHC class II transactivator protein Malignant Neoplasms Measures Mediating Memory Modeling Modification Mus Mutation Non-Hodgkin&apos s Lymphoma Oncogenes Oncogenic Patient Care Pattern Phenotype Play Process Production Proteins Public Health Recurrent disease Relapse Role Stem cells Structure of germinal center of lymph node T cell response T-Cell Activation T-Cell Development T-Cell Proliferation T-Lymphocyte Testing Time Transactivation Transgenic Mice Transgenic Organisms Validation Work YY1 Transcription Factor cytokine differentiated B cell effective therapy epigenetic drug epigenetic regulation experimental study genetic signature histone acetyltransferase human model in vivo in vivo Model inhibitor/antagonist insight mouse model mutant neoplastic cell novel overexpression programs promoter recruit therapeutic target transcription factor tumor tumor microenvironment

项目摘要

Project Summary / Abstract Follicular lymphoma (FL) is an incurable malignancy of germinal center B-cells, in which sequential relapses originate from a tumor cell progenitor with a small number of genetic alterations. We recently defined inactivating mutations of a histone acetyltransferase gene, CREBBP, as an early event in disease genesis following translocation of the BCL2 oncogene. CREBBP inactivation in primary FL tumors silenced a germinal center B- cell transcriptional program that was significantly enriched for genes involved in antigen presentation on MHC class II and targets of the YY1 transcription factor. Reduced antigen presentation was associated with a decreased ability of tumor cells to activate CD4 T-cell proliferation and a reduced number of T-cells within the tumor microenvironment. CREBBP epigenetically regulates gene expression via histone acetylation that is directed via interactions with transcription factors such as CIITA, a central regulator of MHC class II gene expression, and YY1, a key regulator of germinal center B-cell development. We therefore hypothesize that inactivating mutations of CREBBP plays dual roles in promoting lymphomagenesis by driving immune evasion via decreased antigen presentation, and by deregulating B-cell development to allow stalling at the germinal center B-cell stage. To investigate this, we have developed in vitro and in vivo models of CREBBP inactivation using CRISPR-modification of lymphoma cell lines and transgenic mouse models, respectively. Importantly, CRISPR-modified cell lines recapitulate the phenotype of reduced MHC class II expression observed in primary FL tumors, and transgenic mouse models develop FL-like tumors when Crebbp is deleted and Bcl2 is over- expressed specifically within B-cells. We will use these models, in parallel with primary human tumors, to explore the hypothesized mechanistic roles of CREBBP inactivation in lymphomagenesis. Specifically, we will evaluate the capacity for CREBBP inactivation to reduce antigen presentation on MHC class II, and measure the effect that this has on T-cell responses in vitro and in vivo. In addition, we will investigate the role of CREBBP inactivation in reducing the expression of germinal center B-cell genes that are regulated by the YY1 transcription factor, and determine whether this leads to stalled differentiation at the germinal center B-cell stage in vivo using transgenic mouse models. We further hypothesize that these phenotypes are driven by epigenetic alterations, and may therefore potentially be corrected using epigenetic modifying drugs. We will therefore investigate the potential for HDAC inhibitors and EZH2 inhibitors to restore antigen presentation and associated T-cell responses, and to reestablish normal epigenetic and transcriptional programs of B-cell development. Together this work will provide validation for CREBBP inactivation as a key event in the development of FL, define the mechanism by which these genetic events contribute to immune evasion and deregulated B-cell development, and evaluate the use of epigenetic modifying compounds for counteracting these features of CREBBP inactivation. This will contribute important advances in the understanding and treatment of FL.

项目摘要/摘要