Gene Regulatory Network Analysis Predicts Cooperating Transcription Factor Regulons Required for FLT3-ITD+ AML Growth

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2023 Dec 17

PMID 38104314

Authors

Daniel J L Coleman

Peter Keane

Rosario Luque-Martin

Paulynn S Chin

Helen Blair

Luke Ames

Sophie G Kellaway

James Griffin

Elizabeth Holmes

Sandeep Potluri

Salam A Assi

John Bushweller

Olaf Heidenreich

Peter N Cockerill

Constanze Bonifer

Affiliations

Soon will be listed here.

Abstract

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.

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