TY - JOUR TI - Therapeutic resistance in acute myeloid leukemia cells is mediated by a novel ATM/mTOR pathway regulating oxidative phosphorylation AU - Park, Hae J AU - Gregory, Mark A AU - Zaberezhnyy, Vadym AU - Goodspeed, Andrew AU - Jordan, Craig T AU - Kieft, Jeffrey S AU - DeGregori, James A2 - Henske, Elizabeth P A2 - Rathmell, W Kimryn VL - 11 PY - 2022 DA - 2022/10/19 SP - e79940 C1 - eLife 2022;11:e79940 DO - 10.7554/eLife.79940 UR - https://doi.org/10.7554/eLife.79940 AB - 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. KW - AML KW - drug resistance KW - bone marrow JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -