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