{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T12:46:29Z","timestamp":1768567589527,"version":"3.49.0"},"posted":{"date-parts":[[2024,12,18]]},"group-title":"Hematology","reference-count":40,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,12,18]],"date-time":"2024-12-18T00:00:00Z","timestamp":1734480000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,12,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    Germline\n                    <jats:italic>RUNX1<\/jats:italic>\n                    haplodeficiency (RHD) is associated with thrombocytopenia, platelet dysfunction and predisposition to myeloid malignancies. Platelet expression profiling of a RHD patient showed decreased\n                    <jats:italic>F13A1,<\/jats:italic>\n                    encoding for the A subunit of factor XIII, a transglutaminase that cross-links fibrin and induces clot stabilization. FXIII-A is synthesized by hematopoietic cells, megakaryocytes and monocytes.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>\n                    To understand RUNX1 regulation of\n                    <jats:italic>F13A1<\/jats:italic>\n                    expression in platelet\/megakaryocyte and the mechanisms and consequences of decreased\n                    <jats:italic>F13A1<\/jats:italic>\n                    in RHD.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    We performed studies in platelets, HEL cells and human CD34+ cell-derived megakaryocytes including on clot contraction in cells following small inhibitor (si)RNA knockdown (KD) of\n                    <jats:italic>RUNX1<\/jats:italic>\n                    or\n                    <jats:italic>F13A1<\/jats:italic>\n                    .\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Platelet\n                    <jats:italic>F13A1<\/jats:italic>\n                    mRNA and protein were decreased in our index patient and in two siblings from an unrelated family with RHD. Platelet-driven clot contraction was decreased in the patient and affected daughter. Promoter studies in HEL cells showed that\n                    <jats:italic>RUNX1<\/jats:italic>\n                    regulates\n                    <jats:italic>F13A1<\/jats:italic>\n                    transcription; RUNX1 overexpression increased and (si)RNA RUNX1 KD reduced\n                    <jats:italic>F13A1<\/jats:italic>\n                    promoter activity and protein. Following\n                    <jats:italic>RUNX1<\/jats:italic>\n                    or\n                    <jats:italic>F13A1<\/jats:italic>\n                    KD clot contraction by HEL cells was decreased as were FXIII-A surface expression, myosin light chain phosphorylation and PAC1 binding upon activation.\n                    <jats:italic>F13A1<\/jats:italic>\n                    expression and clot contraction were impaired on\n                    <jats:italic>RUNX1<\/jats:italic>\n                    downregulation in human megakaryocytes.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>\n                    RUNX1 regulates platelet-megakaryocyte\n                    <jats:italic>F13A1<\/jats:italic>\n                    expression, which is decreased in RHD, reflecting regulation of a coagulation protein by a hematopoietic transcription factor. Platelet and megakaryocyte clot contraction is decreased in RHD, related to multiple impaired mechanisms including\n                    <jats:italic>F13A1<\/jats:italic>\n                    expression, myosin phosphorylation and \u03b1II\n                    <jats:sub>b<\/jats:sub>\n                    \u03b2\n                    <jats:sub>3<\/jats:sub>\n                    activation.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Scientific category<\/jats:bold>\n                    \u2013 Platelets and thrombopoiesis\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Essentials<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>\n                        RUNX1 regulates expression of FXIII-A chain (\n                        <jats:italic>F13A1)<\/jats:italic>\n                        in megakaryocytes (MK) and platelets.\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        Platelet and MK\n                        <jats:italic>F13A1<\/jats:italic>\n                        expression and clot contraction are decreased in\n                        <jats:italic>RUNX1<\/jats:italic>\n                        deficiency.\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        MK clot contraction, myosin phosphorylation and PAC1-binding are impaired in\n                        <jats:italic>F13A1<\/jats:italic>\n                        deficiency.\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Defective clot contraction in RHD arises from defects in multiple platelet-MK mechanisms.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.1101\/2024.12.17.24318561","type":"posted-content","created":{"date-parts":[[2024,12,18]],"date-time":"2024-12-18T19:01:06Z","timestamp":1734548466000},"source":"Crossref","is-referenced-by-count":0,"title":["Transcription Factor RUNX1 Regulates Coagulation Factor XIII-A (\n                  <i>F13A1<\/i>\n                  ): Decreased Platelet-Megakaryocyte\n                  <i>F13A1<\/i>\n                  Expression and Clot Contraction in\n                  <i>RUNX1<\/i>\n                  Haplodeficiency"],"prefix":"10.64898","author":[{"given":"Fabiola","family":"Del Carpio-Cano","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natthapol","family":"Songdej","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liying","family":"Guan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guangfen","family":"Mao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0525-6008","authenticated-orcid":false,"given":"Lawrence E.","family":"Goldfinger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeremy G.T.","family":"Wurtzel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kiwon","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0439-402X","authenticated-orcid":false,"given":"Michele P","family":"Lambert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7237-3613","authenticated-orcid":false,"given":"Mortimer","family":"Poncz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3078-7778","authenticated-orcid":false,"given":"A.","family":"Koneti Rao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024122510501004000_2024.12.17.24318561v1.1","unstructured":"Deuitch N , Broadbridge E , Cunningham L , Liu P . RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies. In: Adam MP , Feldman J , Mirzaa GM , Pagon RA , Wallace SE , Bean LJH , Gripp KW , Amemiya A , eds. GeneReviews((R)). Seattle (WA), 1993."},{"key":"2024122510501004000_2024.12.17.24318561v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-022-01548-7"},{"key":"2024122510501004000_2024.12.17.24318561v1.3","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-12-689109"},{"key":"2024122510501004000_2024.12.17.24318561v1.4","first-page":"722","article-title":"Runx1\/AML-1 ranks as a master regulator of adult hematopoiesis","volume":"3","year":"2004","journal-title":"Cell Cycle"},{"key":"2024122510501004000_2024.12.17.24318561v1.5","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2023019746"},{"key":"2024122510501004000_2024.12.17.24318561v1.6","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-10-687830"},{"key":"2024122510501004000_2024.12.17.24318561v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/13793"},{"key":"2024122510501004000_2024.12.17.24318561v1.8","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-11-709881"},{"key":"2024122510501004000_2024.12.17.24318561v1.9","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2023011098"},{"key":"2024122510501004000_2024.12.17.24318561v1.10","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2006.02271.x"},{"key":"2024122510501004000_2024.12.17.24318561v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtha.2023.01.023"},{"key":"2024122510501004000_2024.12.17.24318561v1.12","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020006389"},{"key":"2024122510501004000_2024.12.17.24318561v1.13","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2017014274"},{"key":"2024122510501004000_2024.12.17.24318561v1.14","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2021006945"},{"key":"2024122510501004000_2024.12.17.24318561v1.15","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22063055"},{"key":"2024122510501004000_2024.12.17.24318561v1.16","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00016.2010"},{"key":"2024122510501004000_2024.12.17.24318561v1.17","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.122.317164"},{"key":"2024122510501004000_2024.12.17.24318561v1.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.rpth.2022.100023"},{"key":"2024122510501004000_2024.12.17.24318561v1.19","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.117.309271"},{"key":"2024122510501004000_2024.12.17.24318561v1.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtha.2024.07.032"},{"key":"2024122510501004000_2024.12.17.24318561v1.21","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-05-647560"},{"key":"2024122510501004000_2024.12.17.24318561v1.22","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-04-491290"},{"key":"2024122510501004000_2024.12.17.24318561v1.23","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-06-227645"},{"key":"2024122510501004000_2024.12.17.24318561v1.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.rpth.2023.100200"},{"key":"2024122510501004000_2024.12.17.24318561v1.25","doi-asserted-by":"publisher","DOI":"10.1159\/000215140"},{"key":"2024122510501004000_2024.12.17.24318561v1.26","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0609.1980.tb02358.x"},{"key":"2024122510501004000_2024.12.17.24318561v1.27","doi-asserted-by":"publisher","DOI":"10.1172\/JCI75386"},{"key":"2024122510501004000_2024.12.17.24318561v1.28","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-06-652263"},{"key":"2024122510501004000_2024.12.17.24318561v1.29","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1182\/blood.V87.4.1368.bloodjournal8741368","article-title":"Abnormal inside-out signal transduction-dependent activation of GPIIb-IIIa in a patient with impaired pleckstrin phosphorylation","volume":"87","year":"1996","journal-title":"Blood"},{"key":"2024122510501004000_2024.12.17.24318561v1.30","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2003-07-2299"},{"key":"2024122510501004000_2024.12.17.24318561v1.31","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2022017561"},{"key":"2024122510501004000_2024.12.17.24318561v1.32","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-06-583070"},{"key":"2024122510501004000_2024.12.17.24318561v1.33","doi-asserted-by":"publisher","DOI":"10.1111\/jth.15668"},{"key":"2024122510501004000_2024.12.17.24318561v1.34","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2024012979"},{"key":"2024122510501004000_2024.12.17.24318561v1.35","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-06-289850"},{"key":"2024122510501004000_2024.12.17.24318561v1.36","doi-asserted-by":"publisher","DOI":"10.1002\/rth2.12755"},{"key":"2024122510501004000_2024.12.17.24318561v1.37","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2023021545"},{"key":"2024122510501004000_2024.12.17.24318561v1.38","doi-asserted-by":"publisher","DOI":"10.1038\/nature21706"},{"key":"2024122510501004000_2024.12.17.24318561v1.39","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0609.1993.tb00637.x"},{"key":"2024122510501004000_2024.12.17.24318561v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2016.08.021"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.12.17.24318561","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:23:15Z","timestamp":1768508595000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2024.12.17.24318561"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,18]]},"references-count":40,"URL":"https:\/\/doi.org\/10.1101\/2024.12.17.24318561","relation":{},"subject":[],"published":{"date-parts":[[2024,12,18]]},"subtype":"preprint"}}