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。
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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