Perturbed epigenetic transcriptional regulation in AML with IDH mutations causes increased susceptibility to NK cells.
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
09 2023
09 2023
Historique:
received:
23
01
2023
accepted:
10
07
2023
revised:
05
06
2023
medline:
28
8
2023
pubmed:
27
7
2023
entrez:
26
7
2023
Statut:
ppublish
Résumé
Isocitrate dehydrogenase (IDH) mutations are found in 20% of acute myeloid leukemia (AML) patients. However, only 30-40% of the patients respond to IDH inhibitors (IDHi). We aimed to identify a molecular vulnerability to tailor novel therapies for AML patients with IDH mutations. We characterized the transcriptional and epigenetic landscape with the IDH2i AG-221, using an IDH2 mutated AML cell line model and AML patient cohorts, and discovered a perturbed transcriptional regulatory network involving myeloid transcription factors that were partly restored after AG-221 treatment. In addition, hypermethylation of the HLA cluster caused a down-regulation of HLA class I genes, triggering an enhanced natural killer (NK) cell activation and an increased susceptibility to NK cell-mediated responses. Finally, analyses of DNA methylation data from IDHi-treated patients showed that non-responders still harbored hypermethylation in HLA class I genes. In conclusion, this study provides new insights suggesting that IDH mutated AML is particularly sensitive to NK cell-based personalized immunotherapy.
Identifiants
pubmed: 37495775
doi: 10.1038/s41375-023-01972-3
pii: 10.1038/s41375-023-01972-3
pmc: PMC10457197
doi:
Substances chimiques
enasidenib
3T1SS4E7AG
Isocitrate Dehydrogenase
EC 1.1.1.41
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1830-1841Informations de copyright
© 2023. The Author(s).
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