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

• Waleed Minzel ^[1] ; Avanthika Venkatachalam ^[1] ; Avner Fink ^[1]
  1. [1] Hebrew University- Hadassah Medical School
• Localización: Cell, ISSN 0092-8674, Vol. 175, Nº. 1, 2018, págs. 171-185
• Idioma: inglés
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• Resumen

  • 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.