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Through single\u2010cell RNA sequencing and functional assays, we demonstrate that hematopoietic stem and multipotent progenitor cells (HSPCs) in SCA are transcriptionally reprogrammed toward myeloid differentiation. This process is orchestrated by aberrant activation of Type I interferon (IFN\u2010I) signaling, which promotes premature myeloid commitment of hematopoietic stem cells. SCA progenitors further exhibit unexpected responsiveness to granulocyte colony\u2010stimulating factor (G\u2010CSF) through upregulation of CSF3R, resulting in skewed myelopoiesis toward the monocytic lineage. Importantly, hydroxyurea treatment attenuates IFN\u2010I signaling in neutrophils, consistent with its therapeutic role in reducing excessive inflammation and granulopoiesis. Collectively, these findings uncover IFN\u2010I\u2013driven remodeling of hematopoiesis as a fundamental mechanism of leukocytosis and chronic inflammation in SCA, and establish a tractable therapeutic axis to mitigate innate immunity activation in this disease.<\/jats:p>","DOI":"10.1002\/ajh.70277","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T09:02:38Z","timestamp":1773910958000},"page":"1283-1301","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["<scp>IFN<\/scp>\n                    \u2010\n                    <scp>I<\/scp>\n                    \u2010Mediated Transcriptional Reprogramming Drives Myeloid\u2010Skewed Hematopoiesis in Sickle Cell Anemia"],"prefix":"10.1002","volume":"101","author":[{"given":"Marion","family":"Serra","sequence":"first","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, Universit\u00e9 des Antilles, INSERM, EFS, BIGR U1134, Laboratory of 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