A FOXO1-dependent transcription network is a targetable vulnerability of mantle cell lymphomas.
Lymphomas
Oncology
Journal
The Journal of clinical investigation
ISSN: 1558-8238
Titre abrégé: J Clin Invest
Pays: United States
ID NLM: 7802877
Informations de publication
Date de publication:
15 12 2022
15 12 2022
Historique:
received:
04
04
2022
accepted:
21
10
2022
pubmed:
26
10
2022
medline:
17
12
2022
entrez:
25
10
2022
Statut:
epublish
Résumé
Targeting lineage-defined transcriptional dependencies has emerged as an effective therapeutic strategy in cancer treatment. Through screening for molecular vulnerabilities of mantle cell lymphoma (MCL), we identified a set of transcription factors (TFs) including FOXO1, EBF1, PAX5, and IRF4 that are essential for MCL propagation. Integrated chromatin immunoprecipitation and sequencing (ChIP-Seq) with transcriptional network reconstruction analysis revealed FOXO1 as a master regulator that acts upstream in the regulatory TF hierarchy. FOXO1 is both necessary and sufficient to drive MCL lineage commitment through supporting the lineage-specific transcription programs. We further show that FOXO1, but not its close paralog FOXO3, can reprogram myeloid leukemia cells and induce B-lineage gene expression. Finally, we demonstrate that cpd10, a small molecule identified from an enriched FOXO1 inhibitor library, induces a robust cytotoxic response in MCL cells in vitro and suppresses MCL progression in vivo. Our findings establish FOXO1 inhibition as a therapeutic strategy targeting lineage-driven transcriptional addiction in MCL.
Identifiants
pubmed: 36282572
pii: 160767
doi: 10.1172/JCI160767
pmc: PMC9753996
doi:
pii:
Substances chimiques
FOXO1 protein, human
0
Forkhead Box Protein O1
0
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
Subventions
Organisme : NCI NIH HHS
ID : P01 CA214274
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016058
Pays : United States
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