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 尽管旨在开发改进的敏锐分子疗法的努力 髓样白血病（AML），临床结果仍然很差。特别有趣的是必要和选择性 疾病的治疗靶向引发白血病干细胞（LSC）。约旦实验室报告说 LSC在BCL2上与细胞氧化物磷酸化（OXPHOS）的要求相关。定位 BCL2与静脉菌（VEN）与Azacitidine（AZA）结合使用了临床上的重大反应 在新诊断的AML患者中，但是前期难治性和中继疾病仍然是主要的 障碍。值得注意的是，我们表明VEN/AZA耐药AML表达升高的Mcl1蛋白和OXPHOS水平。 此外，约旦实验室最近报告说，MCL1的药物扰动耐药性 标本导致OXPHOS输出的选择性降低以及LSC功能能力降低 通过植入免疫缺陷小鼠的植入测量。对VEN/AZA抗性AML的持续分析突出显示了 线粒体裂变促进DRP1磷酸化以及代谢组的显着增加 富集脂肪酸氧化。这就是我们假设MCL1专门通过 促进线粒体裂变和β-氧化。该提议旨在定义通过 Mcl1独特影响AML的耐药性，我们的研究将在很大程度上利用VEN/AZA耐药性原发性 AML标本以通过裂变和 β-氧化。这些研究的成功完成将产生对 MCL1在控制线粒体形态和脂质代谢中的非经典作用，同时也是 提供抗治疗抗性AML治疗干预的替代方法。