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

将 IKZF1/IKAROS 定义为 MLL-r AML 的癌基因和治疗靶点

• 批准号: 10407467
• 负责人: Jevon Cutler
• 金额: $ 7.23万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10407467
• 关键词: Acute Myelocytic Leukemia; Apoptosis; Binding; Biochemical Genetics; Biology; CRISPR screen; CRISPR/Cas technology; Cell Cycle; Cell Line; ChIP-seq; Chimeric Proteins; Chromatin; Chromosomal Rearrangement; Clinical; Clinical Research; Combined Modality Therapy; Data; Dependence; Development; Discipline; Disease; Down-Regulation; Drug usage; Effectiveness; Evaluation; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Growth; Human; Ikaros protein; Immunomodulators; Knock-out; Lethal Genes; MEIS1 gene; MLL gene; Mass Spectrum Analysis; Menin; Methyltransferase; Myeloid Leukemia; Oncogenes; Oncogenic; Pathway interactions; Patient-Focused Outcomes; Pharmaceutical Preparations; Pharmacology; Phenotype; Play; Post-Translational Regulation; Proliferating; Proteins; Proteome; Proteomics; Regulation; Research; Research Personnel; Resistance; Role; Route; Science; Techniques; Technology; Testing; Thalidomide; Therapeutic Uses; Training Programs; Translations; Treatment Efficacy; Work; XCL1 gene; acute myeloid leukemia cell; base; cancer therapy; career; drug efficacy; efficacy evaluation; experimental study; functional genomics; human model; immunomodulatory therapies; immunoregulation; improved; inhibitor; insight; lenalidomide; leukemia; mouse model; mutant; new therapeutic target; novel; overexpression; patient derived xenograft model; pomalidomide; programs; protein degradation; resistance mechanism; response; screening; skills; small molecule inhibitor; therapeutic target; transcriptome sequencing; whole genome

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.

项目摘要 涉及KMT2A/混合谱系白血病基因（MLL-R）的染色体重排驱动 急性髓样白血病（AML）的侵略性形式的发展和持续增长。小分子 DOTL1甲基转移酶和Menin的抑制剂有效抑制MLL融合驱动的致癌基因 然而，表达早期临床研究表明，抵抗力将限制临床实用性，并突出紧急 需要有效的组合疗法来改善患者预后。在这里，功能性基因组筛选是 在治疗期间阐明抗药性机制和合成致死依赖性 Menin或dot1l的抑制剂，并确定IKZF1/IKAROS是改进的推定治疗靶标 这些药物的功效；暗示了Ikaros在维持MLL-R致癌的重要作用 转录程序。免疫调节（IMID）药物，包括列纳莱度胺，驱动降解的降解 Ikaros，提供了与Menin和Dot1L实施新型组合疗法的直接途径 抑制剂。初步数据表明，Menin抑制和IMID化合物的联合疗法 导致MLL-R AML细胞系的协同杀伤。 该建议的目的是（1）在MLL-R AML的转录程序中表征Ikaros的功能 （2）评估Ikaros作为MLL-R AML的新型治疗靶标的 Menin抑制剂/IMID治疗的组合与Ikaros降解的途径有关。使用 遗传，相互作用，蛋白质组学，小鼠模型和化合物诱导的靶向蛋白的组合 退化方法将使ikaros的致癌贡献和A 对组合治疗有效性的机械理解。这项工作将利用专业知识 在MLL-R AML的生物学以及有关IMID复合开发和优化的协作工作中 MLL-R AML的新有效组合疗法。这项工作将基于并改善新兴的领域 靶向蛋白质降解器的治疗用途。这里描述的工作将继续发展我的 科学技能集，与我的职业生涯目标一致，以剖析白血病的蛋白质调节机制 使用来自多个学科的尖端技术。为此，一个全面的培训计划 开发以最大程度地发挥具有独特方法的独立研究者的潜力 疾病背景下的蛋白质科学研究。