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

Tools

Item Type:	Article
Title:	Small molecules co-targeting CKIα and the transcriptional kinases CDK7/9 control AML in preclinical models
Creators Name:	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. 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
Source:	Cell
ISSN:	0092-8674
Publisher:	Cell Press
Volume:	175
Number:	1
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

Repository Staff Only: item control page