A distinct core regulatory module enforces oncogene expression in KMT2A-rearranged leukemia.
IRF8
KMT2A-rearranged AML
MEF2D
transcriptional addiction
Journal
Genes & development
ISSN: 1549-5477
Titre abrégé: Genes Dev
Pays: United States
ID NLM: 8711660
Informations de publication
Date de publication:
01 03 2022
01 03 2022
Historique:
received:
08
12
2021
accepted:
22
02
2022
pubmed:
19
3
2022
medline:
22
4
2022
entrez:
18
3
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35301220
pii: gad.349284.121
doi: 10.1101/gad.349284.121
pmc: PMC8973843
doi:
Substances chimiques
Interferon Regulatory Factors
0
Myeloid-Lymphoid Leukemia Protein
149025-06-9
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
368-389Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL155144
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA206963
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA010815
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA210030
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA211199
Pays : United States
Informations de copyright
© 2022 Harada et al.; Published by Cold Spring Harbor Laboratory Press.
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