Gene regulatory network analysis predicts cooperating transcription factor regulons required for FLT3-ITD+ AML growth

Acute myeloid leukemia (AML) is a heterogeneous disease caused by different mutations. Previously, we showed that each mutational subtype develops its specific gene regulatory network (GRN) with transcription factors interacting within multiple gene modules, many of which are transcription factor genes themselves. Here, we hypothesize that highly connected nodes within such networks comprise crucial regulators of AML maintenance. We test this hypothesis using FLT3-ITD-mutated AML as a model and conduct an shRNA drop-out screen informed by this analysis. We show that AML-specific GRNs predict crucial regulatory modules required for AML growth. Furthermore, our work shows that all modules are highly connected and regulate each other. The careful multi-omic analysis of the role of one (RUNX1) module by shRNA and chemical inhibition shows that this transcription factor and its target genes stabilize the GRN of FLT3-ITD+ AML and that its removal leads to GRN collapse and cell death. [Display omitted] •A shRNAi drop-out screen for FLT3-ITD AML based on gene regulatory networks•AML-specific GRN analysis predicts regulatory modules required for leukemic growth•Perturbation of key transcription factor modules highlights module connectivity•RUNX1 stabilizes the GRN of FLT3-ITD AML, and its removal leads to cell death Coleman et al. identify a robust gene regulatory network for patients with FLT3-ITD AML, highlighting a crucial role of several different transcription factors including RUNX1 in FLT3-ITD pathology and identifying drug-responsive AML-subtype-specific and overlapping regulatory modules. Their data show identifying AML-subtype-specific GRNs predicts genes required for AML maintenance.