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

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 o...

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Autores principales: Park, Hae J, Gregory, Mark A, Zaberezhnyy, Vadym, Goodspeed, Andrew, Jordan, Craig T, Kieft, Jeffrey S, DeGregori, James
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9645811/
https://www.ncbi.nlm.nih.gov/pubmed/36259537
http://dx.doi.org/10.7554/eLife.79940
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author Park, Hae J
Gregory, Mark A
Zaberezhnyy, Vadym
Goodspeed, Andrew
Jordan, Craig T
Kieft, Jeffrey S
DeGregori, James
author_facet Park, Hae J
Gregory, Mark A
Zaberezhnyy, Vadym
Goodspeed, Andrew
Jordan, Craig T
Kieft, Jeffrey S
DeGregori, James
author_sort Park, Hae J
collection PubMed
description 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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spelling pubmed-96458112022-11-15 Therapeutic resistance in acute myeloid leukemia cells is mediated by a novel ATM/mTOR pathway regulating oxidative phosphorylation Park, Hae J Gregory, Mark A Zaberezhnyy, Vadym Goodspeed, Andrew Jordan, Craig T Kieft, Jeffrey S DeGregori, James eLife Cancer Biology 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. eLife Sciences Publications, Ltd 2022-10-19 /pmc/articles/PMC9645811/ /pubmed/36259537 http://dx.doi.org/10.7554/eLife.79940 Text en © 2022, Park et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cancer Biology
Park, Hae J
Gregory, Mark A
Zaberezhnyy, Vadym
Goodspeed, Andrew
Jordan, Craig T
Kieft, Jeffrey S
DeGregori, James
Therapeutic resistance in acute myeloid leukemia cells is mediated by a novel ATM/mTOR pathway regulating oxidative phosphorylation
title Therapeutic resistance in acute myeloid leukemia cells is mediated by a novel ATM/mTOR pathway regulating oxidative phosphorylation
title_full Therapeutic resistance in acute myeloid leukemia cells is mediated by a novel ATM/mTOR pathway regulating oxidative phosphorylation
title_fullStr Therapeutic resistance in acute myeloid leukemia cells is mediated by a novel ATM/mTOR pathway regulating oxidative phosphorylation
title_full_unstemmed Therapeutic resistance in acute myeloid leukemia cells is mediated by a novel ATM/mTOR pathway regulating oxidative phosphorylation
title_short Therapeutic resistance in acute myeloid leukemia cells is mediated by a novel ATM/mTOR pathway regulating oxidative phosphorylation
title_sort therapeutic resistance in acute myeloid leukemia cells is mediated by a novel atm/mtor pathway regulating oxidative phosphorylation
topic Cancer Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9645811/
https://www.ncbi.nlm.nih.gov/pubmed/36259537
http://dx.doi.org/10.7554/eLife.79940
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