Genome-wide maps of chromatin state in primary MLL-AF9 AML. Genome-wide maps of chromatin state in primary MLL-AF9 AML

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 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 CDK7 and/or CDK9 synergistically stabilize p53, deprive leukemia cells of survival and proliferation-maintaining SE-driven oncogenes, and induce apoptosis. Overall design: H3K27Ac in MLL-AF9 driven mouse AML cells are compared to normal mouse bone cells to identify oncogene-driving super-enhancers (SEs). We further study H3K27Ac and pSer2 RNA polymerase II CTD enrichment in primary MLL-AF9 driven AML cells upon treatment with a small molecule inhibitor (A51) and Control (DMSO).