Understanding resistance mechanisms to protein arginine methyltransransferase Inhibitors in Lymphoma

项目摘要/摘要 非霍奇金淋巴瘤(NHL)是最常见的癌症之一，尽管目前有许多治疗方法 病人从他们的疾病中复发。最近的发现暗示了表观遗传机制和非表观遗传机制 B细胞淋巴瘤患者的经典致癌程序失调。蛋白质精氨酸 甲基转移酶-5(PRMT5)，负责精氨酸对称二甲基化的主要酶 组蛋白和非组蛋白在淋巴肿瘤的发生中起重要作用，控制肿瘤的生长。 转化的B细胞。PRMT5在淋巴瘤中过表达，可能是一种新的治疗靶点 这种病。为了评估是什么调节因子驱动耐药性，我们进行了全基因组CRISPR筛查。 令人惊讶的是，我们发现RNA结合蛋白MUSASHI2(MSI2)是最受欢迎的。MSI2是一种RNA结合 已被认为是与茎相关的蛋白质，在大多数情况下表达最高 侵袭性癌症，但其在B细胞淋巴瘤中的作用尚不清楚。我们的初步数据表明，MSI2 在淋巴瘤中高表达，减少增殖，通过抑制PRMT5进一步减少增殖。 我们还在B细胞淋巴瘤中发现了由PRMT1和PRMT5介导的新的翻译后修饰 并演示了对这些新发现的修改的功能要求。我们建议对此进行研究 新的PRMT-MSI2轴在利用遗传性小鼠模型和人类淋巴瘤细胞系驱动淋巴瘤发生中的作用 和病人样本。此外，我们利用技术创新来研究直接的MSI2靶和 MSI2介导淋巴瘤对PRMT5抑制耐药的机制。这些研究具有广泛的应用前景 对B细胞淋巴瘤中RBPs如何变得失调及其功能受PRMTs控制的影响。

PROJECT SUMMARY/ABSTRACT Non-Hodgkin’s lymphoma (NHL) is among the most common cancers and despite current therapies many patients relapse from their disease. Recent discoveries have implicated epigenetic mechanisms and non- classical oncogenic programs as dysregulated in patients with B-cell lymphoma. Protein arginine methyltransferase-5 (PRMT5), the major enzyme responsible for the arginine symmetric dimethylation of histones and non-histone proteins, plays an important role in lymphomagenesis, controlling the growth of transformed B cells. PRMT5 is overexpressed in lymphoma and may represent a novel therapeutic target for this disease. In order to assess what regulators drive resistance, we performed a genome wide CRISPR screen. Surprisingly, we uncovered the RNA binding protein MUSASHI2 (MSI2) as the top hit. MSI2 is an RNA binding protein that has been implicated as a stem related protein that is the most highly expressed in the most aggressive cancers but its role in B-cell lymphoma is not known. Our preliminary data suggests that MSI2 is highly expressed in lymphomas and reduction reduces proliferation which is further reduced by PRMT5 inhibition. We also discovered new post-translational modifications mediated by PRMT1 and PRMT5 in B-cell lymphoma and demonstrated a functional requirement for these newly discovered modifications. We propose to study this new PRMT-MSI2 axis in driving lymphomagenesis using genetic mouse models, human lymphoma cell lines and patient samples. Furthermore, we utilize technological innovations to study direct MSI2 targets and the mechanism for how MSI2 mediates resistance to PRMT5 inhibition in lymphoma. These studies have broad implication to how RBPs can become dysregulated and their function controlled by PRMTs in B-cell lymphoma.