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

Item Type:Article
Title:Small molecules co-targeting CKIα and the transcriptional kinases CDK7/9 control AML in preclinical models
Creators Name:Minzel, W. and Venkatachalam, A. and Fink, A. and Hung, E. and Brachya, G. and Burstain, I. and Shaham, M. and Rivlin, A. and Omer, I. and Zinger, A. and Elias, S. and Winter, E. and Erdman, P.E. and Sullivan, R.W. and Fung, L. and Mercurio, F. and Li, D. and Vacca, J. and Kaushansky, N. and Shlush, L. and Oren, M. and Levine, R. and Pikarsky, E. and Snir-Alkalay, I. and Ben-Neriah, Y.
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(-/-);Flt3(ITD) AML mouse models and in several patient-derived AML xenograft models, supporting their potential efficacy in curing human leukemia.
Keywords:CKIα Inhibitor, Acute Myeloid Leukemia, p53 Activation, CDK9/P-TEFb Inhibitor, Blocking Transcription Elongation, Super-Enhancer Shutdown, MYC Elimination, MDM2 Abolishment, MCL1 Elimination, Animals, Mice
Publisher:Cell Press
Page Range:171-185.e25
Date:20 September 2018
Official Publication:https://doi.org/10.1016/j.cell.2018.07.045
PubMed:View item in PubMed

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