Understanding the unique dependency for MCL1 in Ven/Aza resistant AML

了解 MCL1 在 Ven/Aza 耐药 AML 中的独特依赖性

• 批准号: 10535785
• 负责人: Mark Jordan Althoff
• 金额: $ 6.92万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-13 至 2025-07-12
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10535785
• 关键词: Ablation; Activities of Daily Living; Acute Myelocytic Leukemia; Azacitidine; BCL2 gene; Biological Assay; Biology; Cell Line; Cells; Clinical; Co-Immunoprecipitations; Colony-forming units; Confocal Microscopy; Data; Dependence; Development; Disease; Disease Resistance; Drug resistance; Dynamin; Electron Microscopy; Engraftment; Enzymes; Exhibits; Fatty Acids; Fractionation; Genetic; Hematologic Neoplasms; Immune; In Vitro; Jordan; Laboratories; Ligation; Link; Long-Chain-Acyl-CoA Dehydrogenase; Mass Spectrum Analysis; Measures; Mediating; Mitochondria; Mitochondrial Matrix; Molecular; Morphology; Mus; Newly Diagnosed; Outcome; Output; Oxidative Phosphorylation; Pathology; Pathway interactions; Patients; Pharmacology; Phenotype; Phosphorylation; Production; Proteins; Recurrent disease; Refractory; Refractory Disease; Relapse; Reporting; Resistance; Role; Sampling; Specimen; Therapeutic Intervention; Xenograft procedure; acute myeloid leukemia cell; crosslink; fatty acid metabolism; fatty acid oxidation; improved; inhibitor; interest; leukemic stem cell; lipid metabolism; lipidomics; long chain fatty acid; metabolomics; molecular targeted therapies; myeloid leukemia cell; novel; oxidation; response; targeted treatment; therapeutic target; therapy resistant; trafficking

PROJECT SUMMARY/ ABSTRACT Despite extensive efforts aimed toward the development of improved molecular therapies targeting acute myeloid leukemia (AML), clinical outcomes remain poor. Of particular interest, is the necessary and selective therapeutic targeting of disease initiating leukemia stem cells (LSC). The Jordan laboratory has reported that LSC are functionally reliant upon BCL2 for cellular oxidative phosphorylation (OXPHOS) requirements. Targeting BCL2 with venetoclax (Ven) in combination with azacitidine (Aza) has clinically delivered significant responses in newly diagnosed AML patients, however both upfront refractory and relapsed diseases are still a major obstacle. Notably, we show that Ven/Aza resistant AML express elevated MCL1 protein and OXPHOS levels. Moreover, the Jordan laboratory have recently reported that pharmacologic perturbation of MCL1 in resistant specimens leads to a selective decrease in OXPHOS output as well as reduced LSC functional ability as measured by engraftment of immune deficient mice. Continued analysis of Ven/Aza resistant AML highlighted a significant increase in mitochondrial fission promoting DRP1 phosphorylation as well as in metabolomic enrichment of fatty acid oxidation. Thus, we hypothesize that MCL1 specifically drives Ven/Aza resistance by promoting mitochondrial fission and β-oxidation. As this proposal aims to define the mechanisms through which MCL1 uniquely influences therapy resistance in AML, our studies will largely utilize Ven/Aza resistant primary AML specimens to interrogate the specific role of MCL1 in regulating mitochondrial function through fission and β-oxidation. Successful completion of these studies will generate a detailed and mechanistic understanding of the non-canonical roles for MCL1 in regulating mitochondrial morphology and lipid metabolism, while also providing alternative approaches for therapeutic intervention in therapy resistant AML.

项目概要/摘要 尽管为了开发针对急性发作的改进的分子疗法做出了广泛的努力 骨髓性白血病（AML）的临床结果仍然很差。特别令人感兴趣的是，必要的和选择性的 针对引发疾病的白血病干细胞（LSC）的治疗靶向。约旦实验室报告称 LSC 在功能上依赖于 BCL2 来满足细胞氧化磷酸化 (OXPHOS) 的需求。瞄准 BCL2 与维奈托克 (Ven) 联合阿扎胞苷 (Aza) 在临床上产生了显着的缓解 然而，在新诊断的 AML 患者中，前期难治性疾病和复发性疾病仍然是主要的 障碍。值得注意的是，我们发现 Ven/Aza 耐药的 AML 表达升高的 MCL1 蛋白和 OXPHOS 水平。 此外，Jordan 实验室最近报道，MCL1 在耐药性中的药理学扰动 样本导致 OXPHOS 输出选择性减少以及 LSC 功能能力降低 通过免疫缺陷小鼠的植入来测量。对 Ven/Aza 耐药 AML 的持续分析强调了 线粒体裂变促进 DRP1 磷酸化以及代谢组学显着增加 脂肪酸氧化富集。因此，我们假设 MCL1 通过以下方式特异性驱动 Ven/Aza 抵抗： 促进线粒体分裂和β-氧化。由于该提案旨在定义机制， MCL1 独特地影响 AML 的治疗耐药性，我们的研究将主要利用 Ven/Aza 耐药的原发性 AML 样本探究 MCL1 通过裂变和调节线粒体功能的具体作用 β-氧化。成功完成这些研究将对以下方面产生详细和机械的理解 MCL1 在调节线粒体形态和脂质代谢中的非典型作用，同时也 为治疗耐药性 AML 的治疗干预提供替代方法。