{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T23:32:14Z","timestamp":1790724734815,"version":"4.1.0"},"reference-count":86,"publisher":"American Society of Hematology","issue":"19","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,5,13]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Patients with familial platelet disorder with a predisposition to myeloid malignancy (FPDMM) harbor germline monoallelic mutations in a key hematopoietic transcription factor, RUNX-1. Previous studies of FPDMM have focused on megakaryocyte (Mk) differentiation and platelet production and signaling. However, the effects of RUNX-1 haploinsufficiency on hematopoietic progenitor cells (HPCs) and subsequent megakaryopoiesis remains incomplete. We studied induced pluripotent stem cell (iPSC)\u2013derived HPCs (iHPCs) and Mks (iMks) from both patient-derived lines and a wild-type (WT) line modified to be RUNX-1 haploinsufficient (RUNX-1+\/\u2212), each compared with their isogenic WT control. All RUNX-1+\/\u2212 lines showed decreased iMk yield and depletion of an Mk-biased iHPC subpopulation. To investigate global and local gene expression changes underlying this iHPC shift, single-cell RNA sequencing was performed on sorted FPDMM and control iHPCs. We defined several cell subpopulations in the Mk-biased iHPCs. Analyses of gene sets upregulated in FPDMM iHPCs indicated enrichment for response to stress, regulation of signal transduction, and immune signaling-related gene sets. Immunoblot analyses in FPDMM iMks were consistent with these findings, but also identified augmented baseline c-Jun N-terminal kinase (JNK) phosphorylation, known to be activated by transforming growth factor-\u03b21 (TGF-\u03b21) and cellular stressors. These findings were confirmed in adult human CD34+-derived stem and progenitor cells (HSPCs) transduced with lentiviral RUNX1 short hairpin RNA to mimic RUNX-1+\/\u2212. In both iHPCs and CD34+-derived HSPCs, targeted inhibitors of JNK and TGF-\u03b21 pathways corrected the megakaryopoietic defect. We propose that such intervention may correct the thrombocytopenia in patients with FPDMM.<\/jats:p>","DOI":"10.1182\/blood.2020006389","type":"journal-article","created":{"date-parts":[[2021,2,12]],"date-time":"2021-02-12T17:18:20Z","timestamp":1613150300000},"page":"2662-2675","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":35,"title":["RUNX-1 haploinsufficiency causes a marked deficiency of megakaryocyte-biased hematopoietic progenitor cells"],"prefix":"10.1182","volume":"137","author":[{"given":"Brian","family":"Estevez","sequence":"first","affiliation":[{"name":"Department of Pediatrics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9829-1445","authenticated-orcid":false,"given":"Sara","family":"Borst","sequence":"additional","affiliation":[{"name":"Department of Pathology, The Children\u2019s Hospital of Philadelphia, Philadelphia, PA;"},{"name":"Department of 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