Small molecules co-targeting CKIα and the transcriptional kinases CDK7/9 control AML in preclinical models Journal Article

Authors: Minzel, W.; Venkatachalam, A.; Fink, A.; Hung, E.; Brachya, G.; Burstain, I.; Shaham, M.; Rivlin, A.; Omer, I.; Zinger, A.; Elias, S.; Winter, E.; Erdman, P. E.; Sullivan, R. W.; Fung, L.; Mercurio, F.; Li, D.; Vacca, J.; Kaushansky, N.; Shlush, L.; Oren, M.; Levine, R.; Pikarsky, E.; Snir-Alkalay, I.; Ben-Neriah, Y.
Article Title: Small molecules co-targeting CKIα and the transcriptional kinases CDK7/9 control AML in preclinical models
Abstract: CKIα ablation induces p53 activation, and CKIα degradation underlies the therapeutic effect of lenalidomide in a pre-leukemia syndrome. Here we describe the development of CKIα inhibitors, which co-target the transcriptional kinases CDK7 and CDK9, thereby augmenting CKIα-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 CKIα 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. Combined stabilization of p53 and inactivation of oncogene-driving super enhancers offers a therapeutic approach for acute myeloid leukemia. © 2018 Elsevier Inc.
Keywords: acute myeloid leukemia; cdk7 inhibitor; blocking transcription elongation; cdk9/p-tefb inhibitor; ckiα inhibitor; mcl1 elimination; mdm2 abolishment; myc elimination; p53 activation; super-enhancer shutdown
Journal Title: Cell
Volume: 175
Issue: 1
ISSN: 0092-8674
Publisher: Cell Press  
Date Published: 2018-09-20
Start Page: 171
End Page: 185.e25
Language: English
DOI: 10.1016/j.cell.2018.07.045
PROVIDER: scopus
PUBMED: 30146162
Notes: Article -- Export Date: 3 December 2018 -- Source: Scopus
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  1. Ross Levine
    463 Levine