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Keywords:

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

Citation:

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 PE, Sullivan RW, Fung L, Mercurio F, Li D, Vacca J, Kaushansky N, Shlush L, Oren M, Levine R, Pikarsky E, Snir-Alkalay I, Ben-Neriah Y. Small Molecules Co-targeting CKIα and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models. Cell 2018;175:171-185.e25.

Date Published:

Sep 20

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.

Notes:

1097-4172Minzel, WaleedVenkatachalam, AvanthikaFink, AvnerHung, EricBrachya, GuyBurstain, IdoShaham, MayaRivlin, AmitaiOmer, ItayZinger, AdarElias, ShlomoWinter, EitanErdman, Paul ESullivan, Robert WFung, LeahMercurio, FrankLi, DansuVacca, JosephKaushansky, NathaliShlush, LiranOren, MosheLevine, RossPikarsky, EliSnir-Alkalay, IritBen-Neriah, YinonL30 HL078257/HL/NHLBI NIH HHS/United StatesR01 CA151949/CA/NCI NIH HHS/United StatesR01 CA216421/CA/NCI NIH HHS/United StatesR01 CA138234/CA/NCI NIH HHS/United StatesR01 CA173636/CA/NCI NIH HHS/United StatesU01 DK104331/DK/NIDDK NIH HHS/United StatesR03 DA026206/DA/NIDA NIH HHS/United StatesU10 CA180827/CA/NCI NIH HHS/United StatesK08 HL082677/HL/NHLBI NIH HHS/United StatesR35 CA197594/CA/NCI NIH HHS/United StatesR33 CA196411/CA/NCI NIH HHS/United StatesP30 CA008748/CA/NCI NIH HHS/United StatesR01 CA169784/CA/NCI NIH HHS/United StatesJournal ArticleResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov'tCell. 2018 Sep 20;175(1):171-185.e25. doi: 10.1016/j.cell.2018.07.045. Epub 2018 Aug 23.

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Last updated on 09/22/2022