Role of KLHL6 inactivation in mature B-cell malignancies

项目摘要 成熟的B细胞肿瘤是男性和女性中第五常见的肿瘤。它们起源于B- 已经进入生发中心并在临床和遗传水平上表现出极大异质性的细胞。这个 蛋白酶体抑制剂Bortezomib和E3泛素连接酶抑制剂来那米特治疗乳腺癌的临床成功 多发性骨髓瘤和B细胞淋巴瘤的治疗使泛素途径成为治疗多发性骨髓瘤和B细胞淋巴瘤的真正靶点 癌症治疗学。因此，定义新的E3连接酶如何在分子水平上发挥作用并研究它们的 在B细胞恶性肿瘤中的作用仍然是一项重要的研究任务，以开发更特异的治疗方法 林荫道。KLHL6是一种功能未知的基因，在慢性等成熟B细胞恶性肿瘤中发生突变 淋巴细胞性白血病、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KLHL6是一种E3泛素连接酶，肿瘤相关突变使其催化失活 活动。这项研究计划的目标是定义KLHL6的分子和细胞功能 关注底物降解，分析体内KLHL6缺失的影响。我们的中心假设是 KLHL6是一种新的肿瘤抑制因子，可能通过调节细胞参与DLBCL和MM的发病 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.