ArticleeLife2022
Therapeutic resistance in acute myeloid leukemia cells is mediated by a novel ATM/mTOR pathway regulating oxidative phosphorylation.
Article in eLife, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 25 citations in OpenAlex.
- Re-evaluating the rationale for targeting oxidative phosphorylation in acute myeloid leukemia.The Biochemical journal · 2026Review
- Genome-Wide CRISPR/Cas9 Screening Identifies Modulators of THZ1 Response in Acute Myeloid Leukemia.Biomedicines · 2026Article
- Statistical Inference of Phenotype-Specific Molecular Mechanisms from Cell Line-Specific Gene Regulatory Networks with Application to Quizartinib Sensitivity.International journal of molecular sciences · 2026Article
- Busulfan resistance in AML is associated with changes in mitochondrial copy number and lipid metabolism.Scientific reports · 2026Article
- Machine Learning-Based Predictive Modeling Maximizes the Efficacy of mTOR/p53 Co-Targeting Therapy Against AML.Cancer science · 2025Article
- High mtDNA content identifies oxidative phosphorylation-driven acute myeloid leukemias and represents a therapeutic vulnerability.Signal transduction and targeted therapy · 2025Article
- Mapping of Functional Metabolic Phenotypes in Acute Myeloid Leukemia.Cancer medicine · 2025Article
- Targeting oncogenic activation of FLT3/SREBP/FASN promotes the therapeutic effect of quizartinib involving disruption of mitochondrial phospholipids.Cell death & disease · 2025Article
- Acute myeloid leukemia mitochondria hydrolyze ATP to support oxidative metabolism and resist chemotherapy.Science advances · 2025Article
- Bone marrow mesenchymal stromal cells support translation in refractory acute myeloid leukemia.Cell reports · 2025Article
- The HOX Gene Family's Role as Prognostic and Diagnostic Biomarkers in Hematological and Solid Tumors.Cancers · 2025Review
- MicroRNA Screening Reveals Upregulation of FoxO-Signaling in Relapsed Acute Myeloid Leukemia Patients.Genes · 2024Article
- Evi1 governs Kdm6b-mediated histone demethylation to regulate the Laptm4b-driven mTOR pathway in hematopoietic progenitor cells.The Journal of clinical investigation · 2024Article
- Feasibility and Safety of Targeting Mitochondria Function and Metabolism in Acute Myeloid Leukemia.Current pharmacology reports · 2024Article
- JR-AB2-011 induces fast metabolic changes independent of mTOR complex 2 inhibition in human leukemia cells.Pharmacological reports : PR · 2024Article
- RNA sequestration in P-bodies sustains myeloid leukaemia.Nature cell biology · 2024Article
- FLT3 tyrosine kinase inhibition modulates PRC2 and promotes differentiation in acute myeloid leukemia.Leukemia · 2024Article
- Disruption of the MYC Superenhancer Complex by Dual Targeting of FLT3 and LSD1 in Acute Myeloid Leukemia.Molecular cancer research : MCR · 2023Article
- FMS-Like Tyrosine Kinase 3 Inhibitors in the Treatment of Acute Myeloid Leukemia: An Update on the Emerging Evidence and Safety Profile.OncoTargets and therapy · 2023Review
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
While leukemic cells are susceptible to various therapeutic insults, residence in the bone marrow microenvironment typically confers protection from a wide range of drugs. Thus, understanding the unique molecular changes elicited by the marrow is of critical importance toward improving therapeutic outcomes. In this study, we demonstrate that aberrant activation of oxidative phosphorylation serves to induce therapeutic resistance in FLT3 mutant human AML cells challenged with FLT3 inhibitor drugs. Importantly, our findings show that AML cells are protected from apoptosis following FLT3 inhibition due to marrow-mediated activation of ATM, which in turn upregulates oxidative phosphorylation via mTOR signaling. mTOR is required for the bone marrow stroma-dependent maintenance of protein translation, with selective polysome enrichment of oxidative phosphorylation transcripts, despite FLT3 inhibition. To investigate the therapeutic significance of this finding, we tested the mTOR inhibitor everolimus in combination with the FLT3 inhibitor quizartinib in primary human AML xenograft models. While marrow resident AML cells were highly resistant to quizartinib alone, the addition of everolimus induced profound reduction in tumor burden and prevented relapse. Taken together, these data provide a novel mechanistic understanding of marrow-based therapeutic resistance and a promising strategy for improved treatment of FLT3 mutant AML patients.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.