Subtype-specific regulatory network rewiring in acute myeloid leukemia

Acute myeloid leukemia (AML) is a heterogeneous disease caused by a variety of mutations in transcription factors, epigenetic regulators and signaling molecules. To determine how different mutant regulators establish AML subtype-specific transcriptional networks we performed a comprehensive global analysis of cis-regulatory element activity and interaction, transcription factor occupancy and gene expression patterns in purified leukemic blast cells. Here, we focussed on specific sub-groups of patients carrying mutations in genes encoding transcription factors (RUNX1, CEBPα) and signaling molecules (FTL3-ITD, RAS, NPM1). Integrated analysis of these data demonstrates that each mutant regulator establishes a specific transcriptional and signaling network unrelated to normal cells sustaining the expression of unique sets of genes required for AML growth and maintenance.