Targeting protein complexes in MLL Leukemia

MLL 白血病中的靶向蛋白质复合物

• 批准号: 7155436
• 负责人: Christine M Palermo
• 金额: $ 3.95万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2007-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7155436
• 关键词: leukemia; proteins

DESCRIPTION (provided by applicant): Acute lymphocytic leukemia (ALL) is a rapidly progressive, life-threatening disease for which certain molecular markers are strongly predictive of poor clinical outcome. One such marker involves reciprocal chromosomal translocations of the mixed-lineage leukemia (MLL) gene at locus 11q23. In over 80% of infant ALL cases, translocations at 11q23 result in the production of a functional chimeric protein consisting of the N-terminal portion of MLL fused to the C- terminal portion of more than 60 fusion partners. The impressive heterogeneity among fusion partners raises difficult questions as to how MLL fusion proteins cause leukemia. It is hypothesized that MLL-mediated leukomogenesis depends upon protein interactions specific for the C-terminal fusion partner, and that these protein interactions serve as potential therapeutic molecular targets. This proposal focuses on identifying protein interactions capable of interacting with the one of the common fusion proteins, MLL-AF9, validating the necessity for these interactions in hematopoietic stem cell transformation, and enhancing the therapeutic potential of a molecularly-targeted chemotherapeutic developed and characterized in our lab through screening of a combinatorial peptide library. The data from these experiments will enhance our understanding of the underlying mechanism of MLL-mediated leukemogenesis, identify novel therapeutic targets, and aid in the development of more effective treatments designed to target the abnormal activity of the MLL-chimeric protein.

描述（由申请人提供）：急性淋巴细胞白血病（Acute lymphocytic leukemia， ALL）是一种进展迅速、危及生命的疾病，某些分子标记物可强烈预测不良临床结果。其中一个这样的标记涉及混合谱系白血病（MLL）基因在11q23位点的染色体易位。在超过80%的婴儿ALL病例中，11q23的易位导致产生功能性嵌合蛋白，该嵌合蛋白由MLL的n端部分融合到60多个融合伙伴的C端部分组成。融合伙伴之间令人印象深刻的异质性提出了MLL融合蛋白如何引起白血病的难题。据推测，mll介导的白血病发生依赖于c端融合伙伴特异性的蛋白质相互作用，这些蛋白质相互作用可作为潜在的治疗分子靶点。本提案的重点是识别能够与常见融合蛋白之一MLL-AF9相互作用的蛋白质相互作用，验证这些相互作用在造血干细胞转化中的必要性，并通过筛选组合肽库来增强我们实验室开发和表征的分子靶向化疗的治疗潜力。这些实验的数据将增强我们对mll介导的白血病发生的潜在机制的理解，确定新的治疗靶点，并有助于开发针对mll嵌合蛋白异常活性的更有效的治疗方法。