AML Relapse After BET Inhibition and Chemotherapy Is Characterized by Myc-Ras Transcriptional Remodeling

Genome-wide analysis of adult and pediatric acute myeloid leukemias (AMLs) revealed distinct mutational profiles characterized by a higher incidence of RAS mutations in young patients. Here we show that the BET inhibitor PLX51107 potently suppresses the growth and promotes apoptosis of NRAS-mutant monocytic AML cell lines, and that these activities are enhanced by co-treatment with the MEK inhibitor PD0325901. Controlled preclinical trials in primary mouse Nras-mutant monocytic AMLs revealed single agent efficacy of PLX51107 that was enhanced by PD0325901. Leukemias that relapsed during treatment developed intrinsic drug resistance characterized by transition to a more primitive state, up-regulation of Myc target genes, and down-regulation of Ras-associated transcriptional programs. AMLs that relapsed after frontline chemotherapy showed similar transcriptional remodeling. These studies demonstrate transcriptional plasticity in primary AMLs that relapse following in vivo treatment with either targeted agents or chemotherapy, and support evaluating BET inhibition in leukemias with monocytic differentiation and RAS mutations. Overall design: To investigate mechanisms of response and resistance to BET and MEK inhibition in acute myeloid leukemia (AML), primary mouse AMLs were transplanted and then exposed in vivo to the BET inhibitor PLX51107 with and without the MEK inhibitor PD0325901 (PD901). Mice were treated and observed daily. Moribund mice were euthanzied and bone marrow was collected. Cells underwent RNA extraction (with or without preceding 24 hour ex vivo exposure drug exposure) for bulk RNA sequencing.