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Azacitidine (AZA), a mainstay therapeutic agent for stem cell transplant\u2013ineligible 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.<\/jats:p>","DOI":"10.1084\/jem.20212228","type":"journal-article","created":{"date-parts":[[2022,7,23]],"date-time":"2022-07-23T02:20:56Z","timestamp":1658542856000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":6,"title":["Megakaryopoiesis impairment through acute innate immune signaling activation by azacitidine"],"prefix":"10.1084","volume":"219","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8824-1666","authenticated-orcid":true,"given":"Ujunwa Cynthia","family":"Okoye-Okafor","sequence":"first","affiliation":[{"name":"Albert Einstein College of Medicine\/Montefiore Medical Center, Department of Cell 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