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

API2 部分在 API2-MALT1 介导的淋巴瘤发生中的多重作用

• 批准号: 7897657
• 负责人: LINDA M MCALLISTER-LUCAS
• 金额: $ 31.91万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7897657
• 关键词: Accounting; Animal Model; Antineoplastic Agents; Apoptosis; Apoptosis Inhibitor; B-Cell Lymphomas; Binding; Biochemical; Bone Marrow; Caspase; Cell Survival; Chimeric Proteins; Chromosomal translocation; Chronic; Complex; Development; Extranodal; Family member; Inflammation; Lymphocyte; Lymphoid Tissue; Lymphoma; Lymphomagenesis; Malignant Neoplasms; Mediating; Modeling; Molecular; Mus; Non-Hodgkin' s Lymphoma; Oncogenic; Pathogenesis; Recurrence; Refractory; Refractory Disease; Research; Resistance; Role; Signal Transduction; Signaling Protein; Site; TRAF2 gene; Testing; Therapeutic Agents; Transplantation; base; design; human BIRC3 protein; in vivo; innovation; insight; metaplastic cell transformation; mouse model; mucosa-associated lymphoid tissue; mucosa-associated lymphoid tissue lymphoma; novel; novel therapeutics; protein protein interaction; small molecule; t(11; 18)(q21; q21); tumor; tumorigenesis

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.

描述(申请人提供)：粘膜相关淋巴组织(MALT)的结外边缘区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)在高达40%的病例中发生，并与治疗耐药和传播倾向有关。这种易位导致了由凋亡抑制因子2(API2)的氨基末端序列和MALT1的羧基末端序列融合而成的嵌合蛋白的产生。尽管有强有力的证据表明t(11；18)在MALT淋巴肿大中起重要作用，但API2-MALT1‘S致癌活性的分子机制尚未确定。本提案中描述的研究旨在阐明API2部分在API2-MALT1依赖的致癌活性中的作用。我们假设API2-MALT1的API2部分通过介导融合蛋白的寡聚化和与调节细胞生存的关键信号蛋白的相互作用而促进肿瘤的发生。我们将结合生化研究、细胞转化分析和小鼠模型来验证这一假设。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，并将为开发新的合理治疗难治性疾病铺平道路。