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Targeting AML MCL-1 re-sensitizes BCL-2 inhibition
CXCR4/CXCL12 axis and CD44 are critical for leukemia- BM stromal microenvironment interactions. Indeed, we found that genetic or pharmacological manipulation of MCL-1, but not BCL-2, in AML cells altered cell migration and adhesion to MSC. In confirmation, in vivo MCL-1, but not BCL-2, inhibition decreased CXCR4 and CD44 levels in BM leukemia cells from PDX mice suggesting a novel func- tion of MCL-1, specifically the regulation of leukemia-stro- ma interactions. The cell intrinsic anti-apoptotic function of MCL-1 may therefore be complemented and enhanced by the cell-extrinsic enhanced adhesion to the BM stroma.
In addition to MCL-1, other mechanisms of intrinsic and acquired venetoclax resistance were reported in recent years.47-50 Although highly effective and statistically signif- icantly extending survival, our combination-treated mice eventually died of leukemia. We observed increased p- AKT levels in leukemia cells collected from these mice, which warrants further investigation.
Collectively, we demonstrated that MCL-1 regulates cell metabolism, leukemia-stroma interactions, and protects leukemia cells from BCL-2 inhibition. MCL-1 inhibition targets multiple cancer cell characteristics and therefore has multifaceted effects in AML. The MCL-1 inhibition- mediated suppression of metabolic activity and inhibition of CXCR4 and CD44 may contribute to its efficacy against AML stem cells in the BM stromal microenviron- ment. Treatment strategies involving combined MCL-1 and BCL-2 inhibition could improve the outcomes in AML patients for whom BCL-2-targeted therapy has failed, which warrants further clinical evaluation.
Disclosures
BZC and MA received research funding from AstraZeneca; JC and LD are employees of AstraZeneca.
Contributions
BZC conceptualized the study, designed the experiments, and wrote the manuscript; PYM and WT performed the experiments and analyzed the data; MW performed the experiments, ana- lyzed the data, and wrote the paper; PLL analyzed the data and edited the paper; DM, VR, and LT performed experiments; JC and LD provided materials, supported study, and edited the paper; MA contributed to the concept development and the exper- imental design and edited the manuscript.
Acknowledgments
We thank Joe Munch and Numsen Hail for editing the manu- script, Natalia Baran for assisting with mitochondrial respiration experiments, and Munazza Noor and Jairo Matthews for pro- viding patient clinical information.
Funding
This work was supported in part by research funding from AstraZeneca (to BZC and MA); and by the Paul and Mary Haas Chair in Genetics (to MA). This work used MD Anderson Cancer Center Flow Cytometry and Cell Imaging, Research Animal Support, Metabolomics, and Characterized Cell Line Core Facilities, supported by the National Institutes of Health Cancer Center Support Grant (P30CA016672). The Metabolomics Core is additionally supported by CPRIT grant RP130397.
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