期刊
HAEMATOLOGICA
卷 107, 期 1, 页码 58-76出版社
FERRATA STORTI FOUNDATION
DOI: 10.3324/haematol.2020.260331
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资金
- AstraZeneca
- Paul and Mary Haas Chair in Genetics
- National Institutes of Health Cancer Center Support Grant [P30CA016672]
- CPRIT grant [RP130397]
MCL-1 and BCL-2 are both overexpressed in acute myeloid leukemia (AML) and play crucial roles in the survival of AML cells and stem cells. Inhibition of MCL-1 enhances the sensitivity to BCL-2 inhibition and improves the efficacy of treatment. Additionally, MCL-1 regulates cell metabolism and leukemia-stromal interactions, providing new mechanisms for AML development.
MCL-1 and BCL-2 are both frequently overexpressed in acute myeloid leukemia (AML) and critical for the survival of AML cells and AML stem cells. MCL-1 is a key factor in venetoclax resistance. Using genetic and pharmacological approaches, we discovered that MCL-1 regulates leukemia cell bioenergetics and carbohydrate metabolisms, including the TCA cycle, glycolysis and pentose phosphate pathway and modulates cell adhesion proteins and leukemia-stromal interactions. Inhibition of MCL-1 sensitizes to BCL-2 inhibition in AML cells and AML stem/progenitor cells, including those with intrinsic and acquired resistance to venetoclax through cooperative release of pro-apoptotic BIM, BAX, and BAK from binding to anti-apoptotic BCL-2 proteins and inhibition of cell metabolism and key stromal microenvironmental mechanisms. The combined inhibition of MCL-1 by MCL-1 inhibitor AZD5991 or CDK9 inhibitor AZD4573 and BCL-2 by venetoclax greatly extended survival of mice bearing patient-derived xenografts established from an AML patient who acquired resistance to venetoclax/ decitabine. These results demonstrate that co-targeting MCL-1 and BCL- 2 improves the efficacy of and overcomes pre-existing and acquired resistance to BCL-2 inhibition. Activation of metabolomic pathways and leukemia-stroma interactions are newly discovered functions of MCL-1 in AML, which are independent from canonical regulation of apoptosis by MCL-1. Our data provide new mechanisms of synergy and a rationale for co-targeting MCL-1 and BCL-2 clinically in patients with AML and potentially other cancers.
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