Roles of Coactivator-Associated Arginine Methyltransferase 1 in B cell activation and lymphomagenesis

共激活剂相关精氨酸甲基转移酶 1 在 B 细胞激活和淋巴瘤发生中的作用

基本信息

批准号：
10598479
负责人：
Michael Richard Green
金额：
$ 44.44万
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：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10598479
关键词：
Acetyltransferase Affect Alleles American Cancer Society Animals Arginine B-Cell Activation B-Cell Development B-Cell Lymphomas B-Cell NonHodgkins Lymphoma B-Lymphocytes Behavior Biological Assay Biological Availability Bromodomain CREBBP gene CRISPR screen CRISPR/Cas technology Cell Line Cell Survival Cellular biology Chemotherapy-Oncologic Procedure Clinical Research Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Complex Critical Pathways Data Development Diagnosis Disease EP300 gene Epigenetic Process Etiology Exhibits Follicular Lymphoma Frequencies Future Gene Expression Profiling Genes Genetic Genetic Transcription Goals Growth Human Immunization Immunotherapy Indolent Knock-out Knockout Mice Knowledge Late Effects Lesion Lymphoma Lymphoma cell Lymphomagenesis Malignant Neoplasms Malignant neoplasm of lung Mediating Methylation Molecular Molecular Biology Mus Mutate Mutation Neoplasms Neoplastic Cell Transformation Non-Hodgkin&apos s Lymphoma Oral Pathogenesis Pathway interactions Patients Pattern Persons Phenotype Play Progressive Disease Protein-Arginine N-Methyltransferase Publishing Recurrent disease Refractory Regulation Residual state Role Small Interfering RNA Somatic Mutation Spleen Structure of germinal center of lymph node Testing Therapeutic Transplantation Work Xenograft Model arginine methyltransferase attenuation cell growth cell type chemotherapy coactivator-associated arginine methyltransferase 1 conditional knockout epigenetic profiling epigenetic therapy histone acetyltransferase human disease inhibitor innovation insight knockout animal large cell Diffuse non-Hodgkin&apos s lymphoma malignant phenotype mouse model mutant next generation sequencing novel patient derived xenograft model premalignant response side effect small molecule inhibitor targeted treatment therapeutic target tumor

项目摘要

PROJECT SUMMARY Follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL) are the most common germinal center (GC)- derived Non-Hodgkin B cell lymphomas (BCLs). Although initially exhibiting an indolent behavior, FLs end up being mostly incurable with 40-50% eventually transforming into an aggressive and lethal form of DLBCL. Although half of DLBCLs can be cured with standard chemotherapy and immunotherapy, many patients are still refractory and succumb to progressive or relapsed disease. In addition, the strong chemotherapy regimens used, even when tolerated, have deleterious side and late effects. Thus, less toxic, targeted therapies are in urgent need for this disease. Recent advances in the molecular biology of DLBCL uncovered critical pathways in the initiation and development of these neoplasms. Of particular importance are next-generation sequencing studies that identified mutations in epigenetic modifiers that led to the development of current active clinical trials using epigenetic therapies in DLBC. Among their highest recurrent disease alleles are somatic mutations affecting two closely related histone acetyltransferase (HAT) genes, Crebbp and EP300. These are frequently monoallelic, within the HAT domain and usually mutually exclusive, suggesting that they 1) might affect a common pathway and 2) residual WT expression of CREBBP and/or EP300 is required for cell survival. We have identified the protein arginine methyltransferase CARM1 (coactivator-associated arginine methyltransferase1) as an important factor to maintain the survival of CREBBP/EP300 mutated BCLs. A potent effective small molecule inhibitor of CARM1 methylation activity has been recently developed and we hypothesize that targeting CARM1 methylation activity in CREBBP/EP300 mutated BCLs causes synthetic lethality. The major goals of this proposal are to determine how inhibition of CARM1 methylation activity affects BCLs harboring CREBBP/EP300 genetic lesions and define the molecular mechanism responsible for the sensitivity of CREBBP/EP300 BCLs to CARM1 inhibition. We anticipate that the results obtained from these studies will impact our current understanding of the pathogenesis of GC-derived BCLs, by providing new insights on the mechanisms of neoplastic transformation. Altogether we ultimately expect that these results will make a strong rationale for future clinical studies using CARM1 inhibitors in Crebbp/Ep300 mutated BCLs.

项目概要滤泡性淋巴瘤 (FL) 和弥漫性大 B 细胞淋巴瘤 (DLBCL) 是最常见的生发中心 (GC) 衍生的非霍奇金 B 细胞淋巴瘤 (BCL)。尽管最初表现出懒惰的行为，但 FL 会结束大部分是无法治愈的，40-50% 最终转化为侵袭性和致命性的 DLBCL。尽管一半的DLBCL可以通过标准化疗和免疫疗法治愈，但许多患者仍然难治性并死于进行性或复发性疾病。此外，采用强效化疗方案，即使可以耐受，也会产生有害的副作用和后期影响。因此，毒性较小的靶向治疗迫在眉睫需要这种疾病。 DLBCL 分子生物学的最新进展揭示了 DLBCL 的关键通路这些肿瘤的发生和发展。特别重要的是下一代测序研究确定了表观遗传修饰剂的突变，导致当前活跃的临床试验的发展 DLBC 的表观遗传疗法。在其复发率最高的疾病等位基因中，体细胞突变影响着两种疾病密切相关的组蛋白乙酰转移酶 (HAT) 基因 Crebbp 和 EP300。这些通常是单等位基因，在 HAT 域内并且通常是相互排斥的，这表明它们 1) 可能影响共同的途径 2) CREBBP 和/或 EP300 的残余 WT 表达是细胞存活所必需的。我们已经确定了蛋白质精氨酸甲基转移酶 CARM1（共激活剂相关精氨酸甲基转移酶 1）作为重要的维持 CREBBP/EP300 突变 BCL 存活的因素。一种有效的小分子抑制剂最近开发了 CARM1 甲基化活性，我们假设针对 CARM1 甲基化 CREBBP/EP300 突变 BCL 的活性导致合成致死。该提案的主要目标是确定 CARM1 甲基化活性的抑制如何影响含有 CREBBP/EP300 基因损伤的 BCL 并确定 CREBBP/EP300 BCL 对 CARM1 敏感性的分子机制抑制。我们预计从这些研究中获得的结果将影响我们目前对 GC 衍生的 BCL 的发病机制，提供了关于肿瘤转化机制的新见解。总而言之，我们最终期望这些结果将为未来的临床研究提供强有力的理由 Crebbp/Ep300 突变 BCL 中的 CARM1 抑制剂。