Study of epigenomic regulation in acute leukemia using kinases inhibitors

Aberrant genetic and epigenetic regulation is a driving force in tumor progression. Here we describe the development of kinase inhibitors, targeting oncogenes and super enhancers (SEs) through blocking the transcriptional kinases CDK7 and CDK9. First, we identified hyper-activated and newly-gained SEs in primary mouse AML cells, in comparison to normal mouse bone marrow. Further, we show that our kinase inhibitors preferentially suppress the transcription elongation of SE-driven oncogenes. These kinase inhibitors were very efficient in multiple preclinical models of AML, but nearly half of treated mice relapse after an initial response. Our preliminary data already implicates MAPK pathway mutation and expression of certain isoforms of the chromatin regulator Brd4 as possible drivers of the inhibitor resistance. Elucidating the complex nature of emerging cancer drug-resistance may offer new possibilities for cancer therapy. We propose that adaptive kinome and epigenomic reprogramming contributes to resistant cell states, possibly by controlling phase-separated transcriptional apparatus and gene expression.