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
基本信息
- 批准号:10535785
- 负责人:
- 金额:$ 6.92万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AblationActivities of Daily LivingAcute Myelocytic LeukemiaAzacitidineBCL2 geneBiological AssayBiologyCell LineCellsClinicalCo-ImmunoprecipitationsColony-forming unitsConfocal MicroscopyDataDependenceDevelopmentDiseaseDisease ResistanceDrug resistanceDynaminElectron MicroscopyEngraftmentEnzymesExhibitsFatty AcidsFractionationGeneticHematologic NeoplasmsImmuneIn VitroJordanLaboratoriesLigationLinkLong-Chain-Acyl-CoA DehydrogenaseMass Spectrum AnalysisMeasuresMediatingMitochondriaMitochondrial MatrixMolecularMorphologyMusNewly DiagnosedOutcomeOutputOxidative PhosphorylationPathologyPathway interactionsPatientsPharmacologyPhenotypePhosphorylationProductionProteinsRecurrent diseaseRefractoryRefractory DiseaseRelapseReportingResistanceRoleSamplingSpecimenTherapeutic InterventionXenograft procedureacute myeloid leukemia cellcrosslinkfatty acid metabolismfatty acid oxidationimprovedinhibitorinterestleukemic stem celllipid metabolismlipidomicslong chain fatty acidmetabolomicsmolecular targeted therapiesmyeloid leukemia cellnoveloxidationresponsetargeted treatmenttherapeutic targettherapy resistanttrafficking
项目摘要
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Mark Jordan Althoff其他文献
Targeting Mitochondrial Calcium Uptake to Eradicate Venetoclax-Resistant Acute Myeloid Leukemia Stem Cells
- DOI:
10.1182/blood-2023-188285 - 发表时间:
2023-11-02 - 期刊:
- 影响因子:
- 作者:
Anagha Inguva Sheth;Krysta Engel;Hunter Tolison;Mark Jordan Althoff;Anna Krug;Maria L Amaya;Shanshan Pei;Tracy Young;Sweta B Patel;Mohd Minhajuddin;Regan Miller;Ian Shelton;Ana Vujovic;Courtney L Jones;Austin E Gillen;Monica Ransom;Sarah Staggs;Clayton Smith;Daniel A. Pollyea;Brett M Stevens - 通讯作者:
Brett M Stevens
Mark Jordan Althoff的其他文献
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{{ truncateString('Mark Jordan Althoff', 18)}}的其他基金
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:
10671482 - 财政年份:2022
- 资助金额:
$ 6.92万 - 项目类别:
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