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

项目总结 滤泡性淋巴瘤(FL)和弥漫大B细胞淋巴瘤(DLBCL)是最常见的生发中心 (GC)起源的非霍奇金B细胞淋巴瘤(BCL)。虽然一开始表现出懒惰的行为，但FLS结束了 UP大多是不治之症，40%-50%最终转化为一种侵袭性和致命性的DLBCL。 尽管一半的DLBCL可以通过标准的化疗和免疫疗法治愈，但许多患者仍然 难治性的和屈从于进行性或复发性疾病的。此外，使用的强化疗方案， 即使在被容忍的情况下，也会产生有害的副作用和后期影响。因此，毒性较小、有针对性的治疗已迫在眉睫。 对这种疾病的需求。DLBCL的分子生物学研究进展揭示了DLBCL的关键途径 这些肿瘤的发生和发展。尤其重要的是下一代测序研究 确定了表观遗传修饰物的突变，导致了目前活跃的临床试验的发展，使用 DLBC的表观遗传疗法。他们复发率最高的等位基因是影响两个人的体细胞突变 与组蛋白乙酰转移酶(HAT)基因密切相关的CREBBP和EP300。这些通常是单等位基因， 在HAT结构域内，通常是相互排斥的，这表明它们1)可能影响一条共同的途径 2)CREBBP和/或EP300的残余WT表达是细胞生存所必需的。我们已经确定了 维持CREBBP/EP300突变BCL存活的因素。一种高效的小分子抗癌药物 最近开发了CARM1甲基化活性，我们假设靶向CARM1甲基化 CREBBP/EP300突变的BCL中的活性导致合成致死。这项建议的主要目标是 确定抑制CARM1甲基化活性如何影响携带CREBBP/EP300基因损伤的BCL 明确了CREBBP/EP300 BCL对CARM1敏感性的分子机制 抑制力。我们预计从这些研究中获得的结果将影响我们目前对 通过对肿瘤转化机制的新见解，揭示了GC来源的BCL的发病机制。 总而言之，我们最终预期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。

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.