{"doi":"10.1084/jem.20212228","title":"Megakaryopoiesis impairment through acute innate immune signaling activation by azacitidine","abstract":"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.","journal":"The Journal of Experimental Medicine","year":2022,"id":268491,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9538,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":930670,"name":"Komal K. Javarappa","orcid":"0000-0002-8168-5595","position":1,"is_corresponding":false},{"id":930671,"name":"Dimitrios Tsallos","orcid":"0000-0002-1639-576X","position":2,"is_corresponding":false},{"id":930672,"name":"Joseph Saad","orcid":"0000-0001-7701-0328","position":3,"is_corresponding":false},{"id":930673,"name":"Daozheng Yang","orcid":"0000-0001-9053-0002","position":4,"is_corresponding":false},{"id":899556,"name":"Chi Zhang","orcid":"0000-0002-9522-3658","position":5,"is_corresponding":false},{"id":930674,"name":"Lumie Benard","orcid":"0000-0002-4445-0578","position":6,"is_corresponding":false},{"id":620189,"name":"Victor Thiruthuvanathan","orcid":"0000-0001-6773-0700","position":7,"is_corresponding":false},{"id":765661,"name":"Sally Cole","orcid":"0000-0002-7660-2732","position":8,"is_corresponding":false},{"id":930675,"name":"Stephen Ruiz","orcid":"0000-0002-1634-9798","position":9,"is_corresponding":false},{"id":930676,"name":"Madhuri Tatiparthy","orcid":"0000-0001-8542-2218","position":10,"is_corresponding":false},{"id":233770,"name":"Gaurav Choudhary","orcid":"0000-0001-9343-5481","position":11,"is_corresponding":false},{"id":663171,"name":"Stefanie DeFronzo","orcid":"0000-0002-5127-3362","position":12,"is_corresponding":false},{"id":247697,"name":"Boris Bartholdy","orcid":"0000-0002-7401-8591","position":13,"is_corresponding":false},{"id":320335,"name":"Céline Pallaud","orcid":"0000-0002-3425-6691","position":14,"is_corresponding":false},{"id":930677,"name":"Pedro Marques Ramos","orcid":"0000-0002-2212-9142","position":15,"is_corresponding":false},{"id":930678,"name":"Aditi Shastri","orcid":"0000-0003-3650-0800","position":16,"is_corresponding":false},{"id":284251,"name":"Amit Verma","orcid":"0000-0001-7592-7693","position":17,"is_corresponding":false},{"id":694824,"name":"Caroline A. Heckman","orcid":"0000-0002-4324-8706","position":18,"is_corresponding":false},{"id":620191,"name":"Britta Will","orcid":"0000-0002-9534-6690","position":19,"is_corresponding":false},{"id":930669,"name":"Ujunwa Cynthia Okoye-Okafor","orcid":"0000-0001-8824-1666","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":null,"created_at":"2026-07-19T00:27:14.088663Z","pmid":"36053753","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}