Dysregulation of ubiquitination in MALT lymphomas

描述（由申请人提供）：粘膜相关淋巴组织（MALT）淋巴瘤是结外组织中最常见的淋巴瘤类型。这些淋巴瘤几乎影响人体的每个器官，其中大多数发生在胃部。MALT淋巴瘤的发病机制与三个独立的染色体易位有关。两个反复易位分别导致Bcl10和MALT1的上调，Bcl10是抗原受体向NF-kB信号传导的关键适配蛋白，MALT1是一种假定的半胱氨酸蛋白酶。与MALT淋巴瘤相关的最常见的染色体易位在细胞凋亡抑制剂2 （C-IAP2）和MALT1之间产生融合蛋白。我们发现C-IAP2是Bcl10的泛素连接酶，该活性在clAP2-MALT1融合中丢失，导致表达这种融合的MALT淋巴瘤中BcMO上调。在MALT1高表达的MALT淋巴瘤中，BcMO表达也上调，说明Bcl10上调是MALT淋巴瘤统一的分子机制。我们计划进一步研究C-IAP2及其相关蛋白的功能和调控，以及它们控制的下游信号事件。这项工作不仅将揭示控制淋巴细胞增殖的信号转导，而且还将确定MALT淋巴瘤的分子机制，这可能导致设计适当的治疗干预这种疾病。

DESCRIPTION (provided by applicant): Mucosa-associated lymphoid tissue (MALT) lymphoma is the most common type of lymphoma that arises in extranodal tissue. These lymphomas affect virtually every organ in the human body, with the majority of them occurring in the stomach. The pathogenesis of MALT lymphomas is associated with three independent chromosomal translocations. Two recurrent translocations lead to the up-regulation of Bcl10, an adapter protein critical for antigen receptor signaling to NF-kB, and MALT1, a putative cysteine protease, respectively. The most frequent chromosomal translocation associated with MALT lymphomas generates a fusion protein between cellular inhibitor of apoptosis 2 (C-IAP2) and MALT1. We have found that C-IAP2 is a ubiquitin ligase for Bcl10, and this activity is lost in the clAP2-MALT1 fusion, causing BcMO upregulation in MALT lymphomas expressing this fusion. BcMO expression is also up-regulated in the MALT lymphomas expressing high levels of MALT1, indicating that Bcl10 up-regulation is a unifying molecular mechanism of MALT lymphomas. We plan to further examine the function and regulation of C-IAP2 and related proteins as well as the downstream signaling events they control. This work will not only uncover the signal transduction governing lymphocyte proliferation but also determine the molecular mechanisms of MALT lymphomas, which may lead to the design of an appropriate therapeutic intervention for this disease.