Defining IKZF1/IKAROS as an oncogene and therapeutic target in MLL-r AML

项目总结 涉及KMT2A/混合血统白血病基因(MLL-r)的染色体重排推动了 一种侵袭性急性髓系白血病(AML)的发展和持续生长。小分子 DOTL1甲基转移酶抑制剂和Menin有效抑制MLL融合驱动的致癌基因 然而，早期的临床研究表明，耐药性将限制临床应用，并突出了一种紧迫的 需要有效的联合治疗来改善患者的预后。这是一项功能性基因组筛选 致力于阐明在治疗期间的耐药性机制和合成致死依赖 Menin或DOT1L的抑制剂并将IKZF1/IKAROS确定为有待改进的潜在治疗靶点 这些药物的疗效；暗示了IKAROS在维持MLL-r致癌方面的重要作用 转录程序。免疫调节(IMID)药物，包括来那度胺，促进了 Ikaros，为实施梅宁和DOT1L的新型联合疗法提供了一条直接途径 抑制剂。初步数据表明，梅宁抑制和一种IMID化合物的联合治疗 结果协同杀伤MLL-r AML细胞系。 该建议旨在(1)表征IKAROS在MLL-r AML转录程序中的功能 (2)评价IKAROS作为治疗MLL-r AML的新靶点，并表征其协同作用 Menin抑制剂/IMiD的联合治疗与IKAROS的降解途径有关。的用法 遗传学、间断性、蛋白质组学、小鼠模型和化合物诱导的靶蛋白的组合 降解方法将使人们能够了解IKAROS和 从机理上理解联合治疗的有效性。这项工作将充分利用专业知识。 在MLL-r AML的生物学和IMID化合物的开发和优化方面的协作工作中建立 治疗MLL-r AML的新有效联合疗法。这项工作将在新兴领域的基础上继续发展和完善。 靶向蛋白质降解剂的治疗用途。这里描述的工作将继续发展我的 一套科学的技能，符合我的职业目标，即剖析白血病的蛋白质调节机制 使用多学科的尖端技术。为此，一项全面的培训方案 旨在最大限度地发挥成为独立调查员的潜力，以独特的方法 疾病背景下的蛋白质科学研究。

PROJECT SUMMARY Chromosomal rearrangements involving the KMT2A/Mixed Lineage Leukemia gene (MLL-r) drive the development and sustained growth of an aggressive form of Acute Myeloid Leukemia (AML). Small molecule inhibitors of the DOTL1 methyltransferase and MENIN effectively suppress MLL-fusion driven oncogenic gene expression, however, early clinical studies indicate that resistance will limit clinical utility and highlights an urgent need for effective combination therapies to improve patient outcomes. Here a functional genomic screening was undertaken to elucidate resistance mechanisms and synthetic lethal dependencies during treatment with inhibitors of either MENIN or DOT1L and identified IKZF1/IKAROS as a putative therapeutic target to improve the efficacy of these drugs; implicating an important role for IKAROS in maintaining the MLL-r oncogenic transcriptional program. The immunomodulatory (IMiD) drugs, including Lenalidomide, drive degradation of IKAROS, providing an immediate route to implementing a novel combination therapy with MENIN and DOT1L inhibitors. Preliminary data suggests that the combination therapy of MENIN inhibition and an IMiD compound results in synergistic killing of MLL-r AML cell lines. This proposal aims to (1) characterize the function of IKAROS within the transcriptional program of MLL-r AML and (2) evaluate IKAROS as a novel therapeutic target in MLL-r AML and characterize the synergistic effect of the combination MENIN inhibitor/IMiD treatment as it relates to pathways of IKAROS degradation. The use of a combination of genetic, interactomic, proteomic, mouse models and compound-induced targeted protein degradation approaches will enable an understanding of the oncogenic contribution of IKAROS and a mechanistic understanding of the effectiveness of combination treatments. This work will capitalize on expertise in the biology of MLL-r AML and collaborative work on IMiD compound development and optimization to establish new effective combination therapies for MLL-r AML. This work will build upon and improve the burgeoning field of therapeutic uses of targeted protein degraders. The worked described here will continue to develop my scientific skill set and is in line with my career goals of dissecting mechanisms of protein regulation in leukemia using cutting edge technologies from multiple disciplines. To that end, a comprehensive training program has been developed to maximize the potential to become an independent investigator with a unique approach toward protein science research in the context of disease.