Abstract
Acute myeloid leukemia with KMT2A (MLL) rearrangements is characterized by specific patterns of gene expression and enhancer architecture, implying unique core transcriptional regulatory circuitry. Here, we identified the transcription factors MEF2D and IRF8 as selective transcriptional dependencies of KMT2A-rearranged AML, where MEF2D displays partially redundant functions with its paralog, MEF2C. Rapid transcription factor degradation followed by measurements of genome-wide transcription rates and superresolution microscopy revealed that MEF2D and IRF8 form a distinct core regulatory module with a narrow direct transcriptional program that includes activation of the key oncogenes MYC, HOXA9, and BCL2. Our study illustrates a mechanism of context-specific transcriptional addiction whereby a specific AML subclass depends on a highly specialized core regulatory module to directly enforce expression of common leukemia oncogenes.
Funder
Damon Runyon-Sohn Pediatric Cancer Fellowship
Alex's Lemonade Stand Foundation
Curing Kids Cancer Foundation
When Everyone Survives Foundation
Pedals for Pediatrics
Children's Cancer Research Fund
Children's Leukemia Research Association
Hyundai Hope on Wheels
Kate Amato Foundation
Boston Children's Hospital Office of Faculty Development
National Institutes of Health
NIH
Swiss National Science Foundation
Lady Tata Memorial Trust
Pediatric Cancer Research Foundation
Julia's Legacy of Hope St. Baldrick's Foundation
Publisher
Cold Spring Harbor Laboratory
Subject
Developmental Biology,Genetics
Cited by
13 articles.
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