期刊
CELL
卷 175, 期 1, 页码 171-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2018.07.045
关键词
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资金
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF)
- Israel Science Foundation (ISF)-Centers of Excellence
- European Research Council [294390 PICHO, 281738 LIVERMICROENV]
- Israel Cancer Research Fund Professorship
- Memorial Sloan Kettering Cancer Center Support Grant [NIH P30 CA008748]
CKI alpha wablation induces p53 activation, and CKI alpha degradation underlies the therapeutic effect of lenalidomide in a pre-leukemia syndrome. Here we describe the development of CKI alpha inhibitors, which co-target the transcriptional kinases CDK7 and CDK9, thereby augmenting CKI alpha-induced p53 activation and its anti-leukemic activity. Oncogene-driving super-enhancers (SEs) are highly sensitive to CDK7/9 inhibition. We identified multiple newly gained SEs in primary mouse acute myeloid leukemia (AML) cells and demonstrate that the inhibitors abolish many SEs and preferentially suppress the transcription elongation of SE-driven on-cogenes. We show that blocking CKI alpha together with CDK7 and/or CDK9 synergistically stabilize p53, deprive leukemia cells of survival and proliferation-maintaining SE-driven oncogenes, and induce apoptosis. Leukemia progenitors are selectively eliminated by the inhibitors, explaining their therapeutic efficacy with preserved hematopoiesis and leukemia cure potential; they eradicate leukemia in MLL-AF9 and Tet2(-/-); Flt3(ITD) AML mouse models and in several patient-derived AML xenograft models, supporting their potential efficacy in curing human leukemia.
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