TY - JOUR
T1 - Small Molecules Co-targeting CKI alpha and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models
AU - Minzel, Waleed
AU - Venkatachalam, Avanthika
AU - Fink, Avner
AU - Hung, Eric
AU - Brachya, Guy
AU - Burstain, Ido
AU - Shaham, Maya
AU - Rivlin, Amitai
AU - Omer, Itay
AU - Zinger, Adar
AU - Elias, Shlomo
AU - Winter, Eitan
AU - Erdman, Paul E.
AU - Sullivan, Robert W.
AU - Fung, Leah
AU - Mercurio, Frank
AU - Li, Dansu
AU - Vacca, Joseph
AU - Kaushansky, Nathali
AU - Shlush, Liran
AU - Oren, Moshe
AU - Levine, Ross
AU - Pikarsky, Eli
AU - Snir-Alkalay, Irit
AU - Ben-Neriah, Yinon
PY - 2018/9/20
Y1 - 2018/9/20
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85056317862&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2018.07.045
DO - 10.1016/j.cell.2018.07.045
M3 - Article
SN - 0092-8674
VL - 175
SP - 171
EP - 185
JO - Cell
JF - Cell
IS - 1
ER -