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

Waleed Minzel, Avanthika Venkatachalam, Avner Fink, Eric Hung, Guy Brachya, Ido Burstain, Maya Shaham, Amitai Rivlin, Itay Omer, Adar Zinger, Shlomo Elias, Eitan Winter, Paul E. Erdman, Robert W. Sullivan, Leah Fung, Frank Mercurio, Dansu Li, Joseph Vacca, Nathali Kaushansky, Liran ShlushMoshe Oren, Ross Levine, Eli Pikarsky, Irit Snir-Alkalay, Yinon Ben-Neriah*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

111 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)171-185
Number of pages15
JournalCell
Volume175
Issue number1
Early online date23 Aug 2018
DOIs
Publication statusPublished - 20 Sept 2018

Funding

Publisher Copyright: © 2018 Elsevier Inc.

All Science Journal Classification (ASJC) codes

  • General Biochemistry,Genetics and Molecular Biology

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