Therapeutic resistance in acute myeloid leukemia cells is mediated by a novel ATM/mTOR pathway regulating oxidative phosphorylation
- University of Colorado Anschutz Medical Campus, United States
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 towards improving therapeutic outcomes. In the present 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 up-regulates 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.
Data availability
All data generated or analyzed during this study are included in manuscript and supporting file. RNA-seq data have been deposited in GEO under accession codes GSE202230.
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Ataxia-telangiectasia cerebellar cortex expressionNCBI Gene Expression Omnibus,GSE61019.
Article and author information
Author details
Funding
National Cancer Institute (Graduate Student Fellowship,NRSA F30CA23197)
- Hae J Park
National Cancer Institute (R35GM118070)
- Jeffrey S Kieft
V Foundation for Cancer Research (T2016-012)
- James DeGregori
St. Baldrick's Foundation (AWD-430131)
- James DeGregori
Leukemia and Lymphoma Society (7020-19)
- Craig T Jordan
Leukemia and Lymphoma Society (7020-19)
- James DeGregori
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experiments were approved by and performed in accordance with guidelines of the Institutional Animal Care and Use Committee at University of Colorado (protocol No. 00170).
Human subjects: Deidentified primary AML studies were obtained with donor consent from patients at the University of Colorado Anschutz Medical Campus (COMIRB protocol #12-0173)
Copyright
© 2022, Park et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Therapeutic resistance in acute myeloid leukemia cells is mediated by a novel ATM/mTOR pathway regulating oxidative phosphorylation
eLife 11:e79940.
https://doi.org/10.7554/eLife.79940
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