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It is characterized by thrombocytopenia, platelet dysfunction, and a predisposition to hematological malignancies. Although FPDMM is a precursor for diseases involving abnormal DNA methylation, the DNA methylation status in FPDMM remains unknown, largely due to a lack of animal models and challenges in obtaining patient-derived samples. Here, using genome editing techniques, we established two lines of human induced pluripotent stem cells (iPSCs) with different FPDMM-mimicking heterozygous <jats:italic>RUNX1<\/jats:italic> mutations. These iPSCs showed defective differentiation of hematopoietic progenitor cells (HPCs) and megakaryocytes (Mks), consistent with FPDMM. The FPDMM-mimicking HPCs showed DNA methylation patterns distinct from those of wild-type HPCs, with hypermethylated regions showing the enrichment of ETS transcription factor (TF) motifs. We found that the expression of <jats:italic>FLI1<\/jats:italic>, an ETS family member, was significantly downregulated in FPDMM-mimicking HPCs with a RUNX1 transactivation domain (TAD) mutation. We demonstrated that FLI1 promoted binding-site-directed DNA demethylation, and that overexpression of <jats:italic>FLI1<\/jats:italic> restored their megakaryocytic differentiation efficiency and hypermethylation status. These findings suggest that FLI1 plays a crucial role in regulating DNA methylation and correcting defective megakaryocytic differentiation in FPDMM-mimicking HPCs with a RUNX1 TAD mutation.<\/jats:p>","DOI":"10.1038\/s41598-024-64829-4","type":"journal-article","created":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T16:04:37Z","timestamp":1718726677000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["FLI1 is associated with regulation of DNA methylation and megakaryocytic differentiation in FPDMM caused by a RUNX1 transactivation domain mutation"],"prefix":"10.1038","volume":"14","author":[{"given":"Yuki","family":"Tanaka","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuri","family":"Nakanishi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erina","family":"Furuhata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken-ichi","family":"Nakada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rino","family":"Maruyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harukazu","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,18]]},"reference":[{"key":"64829_CR1","doi-asserted-by":"publisher","first-page":"4664","DOI":"10.1182\/blood-2005-01-0050","volume":"105","author":"PG Heller","year":"2005","unstructured":"Heller, P. G. et al. Low Mpl receptor expression in a pedigree with familial platelet disorder with predisposition to acute myelogenous leukemia and a novel AML1 mutation. Blood 105, 4664\u20134670 (2005).","journal-title":"Blood"},{"key":"64829_CR2","doi-asserted-by":"publisher","first-page":"4639","DOI":"10.1182\/blood-2008-05-156745","volume":"112","author":"CJ Owen","year":"2008","unstructured":"Owen, C. J. et al. Five new pedigrees with inherited RUNX1 mutations causing familial platelet disorder with propensity to myeloid malignancy. Blood 112, 4639\u20134645 (2008).","journal-title":"Blood"},{"key":"64829_CR3","doi-asserted-by":"publisher","first-page":"1131","DOI":"10.1182\/bloodadvances.2019000901","volume":"4","author":"AL Brown","year":"2020","unstructured":"Brown, A. L. et al. RUNX1-mutated families show phenotype heterogeneity and a somatic mutation profile unique to germline predisposed AML. 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Runx1 is essential for hematopoietic commitment at the hemangioblast stage of development in vitro. Blood 100, 458\u2013466 (2002).","journal-title":"Blood"},{"key":"64829_CR7","doi-asserted-by":"publisher","first-page":"886","DOI":"10.1182\/blood-2003-06-2149","volume":"103","author":"G Lacaud","year":"2004","unstructured":"Lacaud, G., Kouskoff, V., Trumble, A., Schwantz, S. & Keller, G. Haploinsufficiency of Runx1 results in the acceleration of mesodermal development and hemangioblast specification upon in vitro differentiation of ES cells. Blood 103, 886\u2013889 (2004).","journal-title":"Blood"},{"key":"64829_CR8","doi-asserted-by":"publisher","first-page":"2806","DOI":"10.1182\/blood-2009-08-236729","volume":"115","author":"R Sood","year":"2010","unstructured":"Sood, R. et al. Development of multilineage adult hematopoiesis in the zebrafish with a runx1 truncation mutation. 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