Therapeutic resistance in acute myeloid leukemia cells is mediated by a novel ATM/mTOR pathway regulating oxidative phosphorylation

  1. Hae J Park
  2. Mark A Gregory
  3. Vadym Zaberezhnyy
  4. Andrew Goodspeed
  5. Craig T Jordan
  6. Jeffrey S Kieft
  7. James DeGregori  Is a corresponding author
  1. 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.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Hae J Park

    Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7768-9297
  2. Mark A Gregory

    Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Vadym Zaberezhnyy

    Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Andrew Goodspeed

    Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Craig T Jordan

    Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Jeffrey S Kieft

    Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. James DeGregori

    Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, United States
    For correspondence
    James.Degregori@cuanschutz.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1287-1976

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)

Reviewing Editor

  1. Elizabeth P Henske, Brigham And Women's Hospital, United States

Publication history

  1. Preprint posted: February 16, 2022 (view preprint)
  2. Received: May 3, 2022
  3. Accepted: October 17, 2022
  4. Accepted Manuscript published: October 19, 2022 (version 1)
  5. Version of Record published: November 9, 2022 (version 2)

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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  1. Hae J Park
  2. Mark A Gregory
  3. Vadym Zaberezhnyy
  4. Andrew Goodspeed
  5. Craig T Jordan
  6. Jeffrey S Kieft
  7. James DeGregori
(2022)
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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