Megakaryopoiesis impairment through acute innate immune signaling activation by azacitidine.
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
07 11 2022
07 11 2022
Historique:
received:
01
11
2021
revised:
02
04
2022
accepted:
22
07
2022
entrez:
2
9
2022
pubmed:
3
9
2022
medline:
9
9
2022
Statut:
ppublish
Résumé
Thrombocytopenia, prevalent in the majority of patients with myeloid malignancies, such as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), is an independent adverse prognostic factor. Azacitidine (AZA), a mainstay therapeutic agent for stem cell transplant-ineligible patients with MDS/AML, often transiently induces or further aggravates disease-associated thrombocytopenia by an unknown mechanism. Here, we uncover the critical role of an acute type-I interferon (IFN-I) signaling activation in suppressing megakaryopoiesis in AZA-mediated thrombocytopenia. We demonstrate that megakaryocytic lineage-primed progenitors present IFN-I receptors and, upon AZA exposure, engage STAT1/SOCS1-dependent downstream signaling prematurely attenuating thrombopoietin receptor (TPO-R) signaling and constraining megakaryocytic progenitor cell growth and differentiation following TPO-R stimulation. Our findings directly implicate RNA demethylation and IFN-I signal activation as a root cause for AZA-mediated thrombocytopenia and suggest mitigation of TPO-R inhibitory innate immune signaling as a suitable therapeutic strategy to support platelet production, particularly during the early phases of AZA therapy.
Identifiants
pubmed: 36053753
pii: 213441
doi: 10.1084/jem.20212228
pmc: PMC9441716
pii:
doi:
Substances chimiques
Azacitidine
M801H13NRU
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIH HHS
ID : K12CA132783
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA230756
Pays : United States
Organisme : NIDDK NIH HHS
ID : K01 DK105134
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA013330
Pays : United States
Informations de copyright
© 2022 Okoye-Okafor et al.
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