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.

项目总结/摘要 尽管广泛的努力旨在开发针对急性胰腺炎的改进的分子疗法， 骨髓性白血病（AML），临床结果仍然很差。特别令人感兴趣的是， 治疗性靶向疾病起始白血病干细胞（LSC）。约旦实验室报告说， LSC在功能上依赖于BCL 2的细胞氧化磷酸化（OXPHOS）的要求。靶向 BCL 2与维奈托克（Ven）联合阿扎胞苷（Aza）具有临床显著反应 然而，在新诊断的AML患者中，前期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Ven/Aza耐药AML表达升高的MCL 1蛋白和OXPHOS水平。 此外，约旦实验室最近报道，MCL 1的药理学干扰在耐药中起重要作用。 样品导致OXPHOS输出的选择性降低以及LSC功能能力的降低， 通过免疫缺陷小鼠的移植来测量。对Ven/Aza耐药AML的持续分析强调， 线粒体分裂促进DRP 1磷酸化以及代谢组学显著增加 脂肪酸氧化富集。因此，我们假设MCL 1通过以下方式特异性驱动Ven/Aza抗性： 促进线粒体分裂和β-氧化。由于本提案旨在确定机制， MCL 1独特地影响AML的治疗耐药性，我们的研究将在很大程度上利用Ven/Aza耐药的原发性 AML标本，以询问MCL 1在通过分裂和凋亡调节线粒体功能中的特定作用。 β-氧化。这些研究的成功完成将产生一个详细的和机械的理解 MCL 1在调节线粒体形态和脂质代谢中的非经典作用，同时还 为治疗耐药AML的治疗干预提供了替代方法。