Role of KLHL6 inactivation in mature B-cell malignancies

项目摘要 成熟B细胞肿瘤是男性和女性中第五常见的肿瘤。它们来自于B- 已经进入生发中心的细胞，在临床和遗传水平上表现出很大的异质性。的 蛋白酶体抑制剂硼替佐米和E3泛素连接酶抑制剂来那度胺的临床成功 多发性骨髓瘤和B细胞淋巴瘤的治疗已经使泛素途径成为真正的靶点， 癌症治疗学因此，定义新的E3连接酶如何在分子水平上起作用并研究它们的功能， 在B细胞恶性肿瘤中的作用仍然是一个重要的研究任务，以开发更特异的治疗方法。 大道。KLHL 6是一种功能未知的基因，在成熟B细胞恶性肿瘤中发生突变，如慢性乙型肝炎。 淋巴细胞白血病、弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤和多发性骨髓瘤。我们有 证明KLHL 6是一种E3泛素连接酶，癌症相关突变使其催化活性降低。 活动本研究计划的目标是确定KLHL 6的分子和细胞功能， 关于底物降解，并分析KLHL 6-损失在体内的影响。我们的核心假设是， KLHL 6是一种新的肿瘤抑制因子，可能通过调节细胞凋亡而参与DLBCL和MM的发病机制。 增殖、分化和存活。

Project Summary Mature B-cell neoplasms are the fifth most common neoplasm in both males and females. They arise from B- cells that have entered germinal centers and display great heterogeneity at the clinical and genetic levels. The clinical success of proteasome inhibitors, bortezomib, and E3 ubiquitin ligase inhibitors, lenalinomide for the treatment of multiple myeloma and B-cell lymphomas has made the Ubiquitin pathway a bona fide target for cancer therapeutics. Thus, defining how novel E3 ligases function at a molecular level and investigating their role in B-cell malignancies remains a major research imperative in order to develop more specific therapeutic avenues. KLHL6 is a gene of unknown function that is mutated in mature B-cell malignancies such as chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and multiple myeloma. We have demonstrated that KLHL6 is an E3 ubiquitin ligase and cancer-associated mutations inactivate its catalytic activity. The goals of this research proposal are to define the molecular and cellular functions of KLHL6 with regards substrate degradation and analyze the effects of KLHL6-loss in vivo. Our central hypothesis is that KLHL6 is novel tumor suppressor that may contribute to the pathogenesis of DLBCL and MM by regulating cell proliferation, differentiation and survival.