Dysregulation of ubiquitination in MALT lymphomas

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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.