Unleashing Cell-Intrinsic Inflammation as a Strategy to Kill AML Blasts.
Journal
Cancer discovery
ISSN: 2159-8290
Titre abrégé: Cancer Discov
Pays: United States
ID NLM: 101561693
Informations de publication
Date de publication:
06 07 2022
06 07 2022
Historique:
received:
16
07
2021
revised:
08
03
2022
accepted:
06
04
2022
pubmed:
12
4
2022
medline:
9
7
2022
entrez:
11
4
2022
Statut:
ppublish
Résumé
Leukemic blasts are immune cells gone awry. We hypothesized that dysregulation of inflammatory pathways contributes to the maintenance of their leukemic state and can be exploited as cell-intrinsic, self-directed immunotherapy. To this end, we applied genome-wide screens to discover genetic vulnerabilities in acute myeloid leukemia (AML) cells implicated in inflammatory pathways. We identified the immune modulator IRF2BP2 as a selective AML dependency. We validated AML cell dependency on IRF2BP2 with genetic and protein degradation approaches in vitro and genetically in vivo. Chromatin and global gene-expression studies demonstrated that IRF2BP2 represses IL1β/TNFα signaling via NFκB, and IRF2BP2 perturbation results in an acute inflammatory state leading to AML cell death. These findings elucidate a hitherto unexplored AML dependency, reveal cell-intrinsic inflammatory signaling as a mechanism priming leukemic blasts for regulated cell death, and establish IRF2BP2-mediated transcriptional repression as a mechanism for blast survival. This study exploits inflammatory programs inherent to AML blasts to identify genetic vulnerabilities in this disease. In doing so, we determined that AML cells are dependent on the transcriptional repressive activity of IRF2BP2 for their survival, revealing cell-intrinsic inflammation as a mechanism priming leukemic blasts for regulated cell death. See related commentary by Puissant and Medyouf, p. 1617. This article is highlighted in the In This Issue feature, p. 1599.
Identifiants
pubmed: 35405016
pii: 694259
doi: 10.1158/2159-8290.CD-21-0956
pmc: PMC9308469
mid: NIHMS1798362
doi:
Substances chimiques
NF-kappa B
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
Pagination
1760-1781Subventions
Organisme : NCI NIH HHS
ID : K99 CA263161
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA206963
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA211404
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA210030
Pays : United States
Organisme : NCI NIH HHS
ID : K22 CA258805
Pays : United States
Organisme : NCI NIH HHS
ID : K08 CA222684
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
©2022 American Association for Cancer Research.
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