Multiple Roles of the API2 Moiety in API2-MALT1-Mediated Lymphomagenesis

描述（由申请人提供）：结外边缘区粘膜相关淋巴组织（MALT）的b细胞淋巴瘤占所有非霍奇金淋巴瘤的7- 8%。这种肿瘤发生在通常没有淋巴组织的部位，但在淋巴瘤发病前由于慢性炎症而获得有组织的淋巴组织。复发性染色体易位t(11;18)（q21;q21）发生在高达40%的病例中，并与治疗耐药性和传播倾向有关。这种易位导致产生由凋亡抑制剂2 （API2）的氨基末端序列与MALT1的羧基末端序列融合组成的嵌合蛋白。尽管有强有力的证据表明t（11;18）在MALT淋巴瘤形成中起重要作用，但API2-MALT1致癌活性的分子机制尚未明确。本提案中描述的研究旨在阐明API2片段在API2- malt1依赖的致癌活性中的作用。我们假设API2- malt1的API2片段通过介导融合蛋白的寡聚化和与调节细胞存活的关键信号蛋白相互作用来促进肿瘤的发生。我们将结合生化研究、细胞转化分析和小鼠模型来检验这一假设。这项研究将进一步加深我们对炎症和癌症之间复杂关系的理解。预期的结果将为MALT淋巴瘤的分子发病机制提供重要的见解，并将为难治性疾病的新型合理疗法的发展铺平道路。

DESCRIPTION (provided by applicant): Extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) accounts for 7- 8% of all non-Hodgkin lymphomas. This tumor arises in sites that are normally devoid of lymphoid tissue, but which acquire organized lymphoid tissue as a result of chronic inflammation prior to the onset of lymphoma. The recurrent chromosomal translocation t(11;18)(q21;q21) occurs in up to 40% of cases and is associated with treatment resistance and tendency to disseminate. This translocation results in the creation of a chimeric protein composed of amino terminal sequences of Inhibitor of Apoptosis 2 (API2) fused to carboxy terminal sequences of MALT1. Despite strong evidence for an important role for t(11;18) in MALT lymphomagenesis, the molecular mechanisms underlying API2-MALT1's oncogenic activity have not been defined. The studies described in this proposal are aimed at elucidating the role of the API2 moiety in API2-MALT1-dependent oncogenic activity. We hypothesize that the API2 moiety of API2-MALT1 contributes to oncogenesis by mediating oligomerization of the fusion protein and by interacting with critical signaling proteins that regulate cell survival. We will use a combination of biochemical studies, cellular transformation analyses and mouse models to test this hypothesis. This research will further our understanding of the complex relationship between inflammation and cancer. The anticipated results will provide significant insight into the molecular pathogenesis of MALT lymphoma and will pave the way toward the development of novel rational therapies for refractory disease.