{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T05:39:40Z","timestamp":1790746780998,"version":"4.1.0"},"reference-count":53,"publisher":"American Society of Hematology","issue":"3","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,1,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Heterozygous defects in runt-related transcription factor 1 (RUNX1) are causative of a\u00a0familial platelet disorder with associated myeloid malignancy (FPDMM). Because RUNX1-deficient animal models do not mimic bleeding disorder or leukemic risk associated with FPDMM, development of a proper model system is critical to understanding the underlying mechanisms of the observed phenotype and to identifying therapeutic interventions. We previously reported an in\u00a0vitro megakaryopoiesis system comprising human CD34+ hematopoietic stem and progenitor cells that recapitulated the FPDMM quantitative megakaryocyte defect through a decrease in RUNX1 expression via a lentiviral short hairpin RNA strategy. We now show that shRX-megakaryocytes have a marked reduction in agonist responsiveness. We then infused shRX-megakaryocytes into immunocompromised NOD scid gamma (NSG) mice and demonstrated that these megakaryocytes released fewer platelets than megakaryocytes transfected with a nontargeting shRNA, and these platelets had a diminished half-life. The platelets were also poorly responsive to agonists, unable to correct thrombus formation in NSG mice homozygous for a R1326H mutation in von Willebrand Factor (VWFR1326H), which switches the species-binding specificity of the VWF from mouse to human glycoprotein Ib\u03b1. A small-molecule inhibitor RepSox, which blocks the transforming growth factor \u03b21 (TGF\u03b21) pathway and rescued defective megakaryopoiesis in\u00a0vitro, corrected the thrombopoietic defect, defects in thrombus formation and platelet half-life, and agonist response in NSG\/VWFR1326H mice. Thus, this model recapitulates the defects in FPDMM megakaryocytes and platelets, identifies previously unrecognized defects in thrombopoiesis and platelet half-life, and demonstrates for the first time, reversal of RUNX1 deficiency\u2013induced hemostatic defects by a drug.<\/jats:p>","DOI":"10.1182\/blood.2022017561","type":"journal-article","created":{"date-parts":[[2022,10,11]],"date-time":"2022-10-11T21:57:02Z","timestamp":1665525422000},"page":"260-270","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":20,"title":["RUNX1-deficient human megakaryocytes demonstrate thrombopoietic and platelet half-life and functional defects"],"prefix":"10.1182","volume":"141","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1340-3602","authenticated-orcid":false,"given":"Kiwon","family":"Lee","sequence":"first","affiliation":[{"name":"1Division of Hematology, Children\u2019s Hospital of Philadelphia, Philadelphia, 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