Acute Myeloid Leukemia Relapse after Bromodomain Inhibitor Treatment or Chemotherapy is Characterized by Myc-Ras Transcriptional Remodeling

Adult and pediatric acute myeloid leukemias (AMLs) harbor distinct mutational profiles, including a higher incidence of RAS and other signaling mutations in young patients. Here we show that the BET inhibitor PLX51107 potently suppresses the growth of NRAS -mutant 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 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.