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.

项目摘要/摘要 尽管针对急性白血病的改进分子疗法的开发做出了广泛的努力 髓系白血病(AML)，临床结果仍然很差。特别值得注意的是，是必要的和有选择性的 以致病白血病干细胞(LSC)为靶向的治疗。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)的要求。瞄准 万乃馨(Ven)联合氮杂西汀(Aza)对BCL2的临床疗效显著 然而，在新诊断的急性髓细胞白血病患者中，难治性和复发性疾病仍然是主要的 障碍。值得注意的是，我们发现对Ven/Aza耐药的AML表达MCL1蛋白和OXPHOS水平升高。 此外，约旦实验室最近报告说，MCL1在耐药中的药理扰动 标本导致OXPHOS输出的选择性减少以及LSC功能能力的降低 通过植入免疫缺陷小鼠来衡量。对Ven/Aza耐药AML的持续分析强调了 线粒体分裂促进Drp1磷酸化以及代谢组的显著增加 富含脂肪酸的氧化。因此，我们假设MCL1通过以下方式特异性地驱动Ven/aza抗性 促进线粒体分裂和β氧化。由于这项提案旨在定义通过哪些机制 MCL1独一无二地影响AML的治疗耐药性，我们的研究将主要利用Ven/Aza耐药的原发病例 急性髓系白血病标本询问MCL1通过分裂和转录调节线粒体功能的具体作用 β-氧化。成功完成这些研究将产生对以下问题的详细和机械性的理解 MCL1在调节线粒体形态和脂质代谢中的非典型作用，同时也 为耐药AML的治疗干预提供替代方法。