Role of KLHL6 inactivation in mature B-cell malignancies

项目摘要 弥漫大B细胞淋巴瘤(DLBCL)是最常见的非霍奇金淋巴瘤亚型，占 每年约有32,000例新病例，并导致40%以上的病例死亡。这项建议旨在 探讨成熟B细胞癌中突变基因KLHL6与DLBCL的生物学意义 表现出最高的变异率。KLHL6组装成具有功能的cullin环泛素连接酶 (CRL)复合体和癌症相关突变抑制KLHL6与CULLIN3的相互作用，导致 转移泛素链的活性。在这项提案中，我们研究了KLHL6作为一种主要调节因子和肿瘤 凹槽信号的抑制器。小鼠细胞自主性和耐药性的研究 DLBCL模型以及患者来源的DLBLC异种移植将被追寻。在我们的数据基础上， 这一提议的中心假设是，KLHL6功能的放松对淋巴增生症至关重要 并影响治疗。因此，我们的目标是在DLBCL(Aim1)的小鼠模型中模拟Khll6的丢失，我们将 研究Notch通路受损对B细胞受体抑制治疗效果的影响 DLBCL(AIM2)。总之，本研究旨在探讨DLBCL的发病机制和治疗方法。这个 蛋白酶体抑制剂、Bortezomib和E3泛素连接酶胶治疗慢性阻塞性肺疾病的临床成功 血液疾病使泛素途径成为癌症治疗的真正靶点。因此， 在分子水平上定义新的E3连接酶的功能并研究它们在炎症中的作用是至关重要的 以开发更具体的治疗途径。

Project Summary Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma accounting for about 32,000 new cases per year and leading to death in over 40% of cases. This proposal seeks to investigate the biological significance of KLHL6, a gene mutated in mature B-cell cancers, with DLBCL displaying the highest rate of mutations. KLHL6 assembles into a functional CULLIN-RING Ubiquitin ligase (CRL) complex and cancer-associated mutations inhibit KLHL6 interaction to CULLIN3, resulting in loss of activity to transfer ubiquitin chains. In this proposal, we investigate KLHL6 as a master regulator and tumor suppressor of the NOTCH signaling. An investigation of the cell autonomous and drug resistance in murine model of DLBCL as well as patient derived DLBLC xenotransplants will be pursed. Building up on our data, the central hypothesis of this proposal is that deregulation of the KLHL6 function is crucial to lymphomagenesis and impacts therapy. Thus, we aim in modeling loss of Khll6 in a mouse model of DLBCL (Aim1) and we will study how impairment of the NOTCH pathway impacts the therapeutic efficacy of B-cell receptor inhibition in DLBCL (Aim2). Overall, this proposal investigates the mechanisms of DLBCL pathogenesis and treatment. The clinical success of proteasome inhibitors, bortezomib, and E3 ubiquitin ligase glues for the treatment of hematologic diseases 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 inflammation is critical in order to develop more specific therapeutic avenues.