Small Molecules Co-targeting CKI? and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models.

ABSTRACT: CKI? ablation induces p53 activation, and CKI? degradation underlies the therapeutic effect of lenalidomide in a pre-leukemia syndrome. Here we describe the development of CKI? inhibitors, which co-target the transcriptional kinases CDK7 and CDK9, thereby augmenting CKI?-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 oncogenes. We show that blocking CKI? 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-/-;Flt3ITD AML mouse models and in several patient-derived AML xenograft models, supporting their potential efficacy in curing human leukemia.

SUBMITTER: Minzel W 

PROVIDER: S-EPMC6701634 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature