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

项目摘要 滤泡性淋巴瘤（FL）和弥漫性大B细胞淋巴瘤（DLBCL）是最常见的生殖中心 (GC)-来源的非霍奇金B细胞淋巴瘤（BCL）。虽然最初表现出懒惰的行为， 大多数是无法治愈的，40-50%最终转化为侵袭性和致命的DLBCL形式。 尽管半数DLBCL可以通过标准化疗和免疫治疗治愈，但许多患者仍需接受化疗和免疫治疗。 难治性的，并屈服于进行性或复发性疾病。此外，所使用的强有力的化疗方案， 即使在耐受的情况下，也具有有害的副作用和迟发效应。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因子的突变，导致了目前正在进行的临床试验的发展， DLBC的表观遗传疗法。在他们最高复发率的疾病等位基因中， 密切相关的组蛋白乙酰转移酶（HAT）基因，Crebbp和EP 300。它们通常是单等位基因的， 在HAT结构域内，通常相互排斥，表明它们1）可能影响共同的途径 和2）CREBBP和/或EP 300的残余WT表达是细胞存活所需的。我们已经确定了 蛋白质精氨酸甲基转移酶CARM 1（coactivator-associated arginine methyltransferase 1）作为一种重要的 这是维持CREBBP/EP 300突变BCL存活的因素。一种强效的小分子抑制剂， CARM 1甲基化活性是最近开发的，我们假设靶向CARM 1甲基化 CREBBP/EP 300突变BCL中的活性导致合成致死性。该提案的主要目标是 确定CARM 1甲基化活性的抑制如何影响携带CREBBP/EP 300遗传病变的BCL 并确定CREBBP/EP 300 BCL对CARM 1敏感性的分子机制 抑制作用我们预计，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，通过提供新的见解肿瘤转化的机制。 总之，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依据， Crebbp/Ep 300突变BCL中的CARM 1抑制剂。

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.