{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T09:03:01Z","timestamp":1792918981380,"version":"4.5.0"},"reference-count":27,"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>Germ line loss-of-function heterozygous mutations in the RUNX1 gene cause familial platelet disorder with associated myeloid malignancies (FPDMM) characterized by thrombocytopenia and a life-long risk of hematological malignancies. Although gene therapies are being considered as promising therapeutic options, current preclinical models do not recapitulate the human phenotype and are unable to elucidate the relative fitness of mutation-corrected and RUNX1-heterozygous mutant hematopoietic stem and progenitor cells (HSPCs) in\u00a0vivo long term. We generated a rhesus macaque with an FPDMM competitive repopulation model using CRISPR\/Cas9 nonhomologous end joining editing in the RUNX1 gene and the AAVS1 safe-harbor control locus. We transplanted mixed populations of edited autologous HSPCs and tracked mutated allele frequencies in blood cells. In both animals, RUNX1-edited cells expanded over time compared with AAVS1-edited cells. Platelet counts remained below the normal range in the long term. Bone marrows developed megakaryocytic dysplasia similar to human FPDMM, and CD34+ HSPCs showed impaired in\u00a0vitro megakaryocytic differentiation, with a striking defect in polyploidization. In conclusion, the lack of a competitive advantage for wildtype or control-edited HSPCs over RUNX1 heterozygous\u2013mutated HSPCs long term in our preclinical model suggests that gene correction approaches for FPDMM will be challenging, particularly to reverse myelodysplastic syndrome\/ acute myeloid leukemia predisposition and thrombopoietic defects.<\/jats:p>","DOI":"10.1182\/blood.2022018193","type":"journal-article","created":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T21:07:42Z","timestamp":1667423262000},"page":"231-237","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":12,"title":["A <i>RUNX1<\/i>-FPDMM rhesus macaque model reproduces the human phenotype and predicts challenges to curative gene therapies"],"prefix":"10.1182","volume":"141","author":[{"given":"Byung-Chul","family":"Lee","sequence":"first","affiliation":[{"name":"1Translational Stem Cell Biology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifan","family":"Zhou","sequence":"additional","affiliation":[{"name":"1Translational Stem Cell Biology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD"},{"name":"2Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Puddicombe Way, Cambridge, United Kingdom"},{"name":"3Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica","family":"Bresciani","sequence":"additional","affiliation":[{"name":"4Oncogenesis and Development Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neval","family":"Ozkaya","sequence":"additional","affiliation":[{"name":"5Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina","family":"Dulau-Florea","sequence":"additional","affiliation":[{"name":"6Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blake","family":"Carrington","sequence":"additional","affiliation":[{"name":"7Zebrafish Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae-Hoon","family":"Shin","sequence":"additional","affiliation":[{"name":"1Translational Stem Cell Biology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD"},{"name":"8Department of Laboratory Animal Medicine, College of Veterinary Medicine, Jeju National University, Jeju, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6429-439X","authenticated-orcid":false,"given":"Valentina","family":"Baena","sequence":"additional","affiliation":[{"name":"9Electron Microscopy Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5825-9782","authenticated-orcid":false,"given":"Zulfeqhar A.","family":"Syed","sequence":"additional","affiliation":[{"name":"9Electron Microscopy Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3538-5444","authenticated-orcid":false,"given":"So Gun","family":"Hong","sequence":"additional","affiliation":[{"name":"1Translational Stem Cell Biology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Zhen","sequence":"additional","affiliation":[{"name":"4Oncogenesis and Development Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine R.","family":"Calvo","sequence":"additional","affiliation":[{"name":"6Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6779-025X","authenticated-orcid":false,"given":"Paul","family":"Liu","sequence":"additional","affiliation":[{"name":"4Oncogenesis and Development Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia E.","family":"Dunbar","sequence":"additional","affiliation":[{"name":"1Translational Stem Cell Biology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"issue":"4","key":"2023082419142890000_bib1","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1053\/j.seminhematol.2014.08.001","article-title":"Inherited predisposition to acute myeloid leukemia","volume":"51","author":"Godley","year":"2014","journal-title":"Semin Hematol: Elsevier"},{"issue":"21","key":"2023082419142890000_bib2","doi-asserted-by":"crossref","first-page":"1882","DOI":"10.1182\/blood.2019003357","article-title":"High frequency of germline RUNX1 mutations in patients with RUNX1-mutated AML","volume":"135","author":"Simon","year":"2020","journal-title":"Blood"},{"issue":"2","key":"2023082419142890000_bib3","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1038\/13793","article-title":"Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia","volume":"23","author":"Song","year":"1999","journal-title":"Nat Genet"},{"issue":"2","key":"2023082419142890000_bib4","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1053\/j.seminhematol.2016.11.003","article-title":"Recognition of familial myeloid neoplasia in adults","volume":"54","author":"Brown","year":"2017","journal-title":"Semin Hematol: Elsevier"},{"issue":"11","key":"2023082419142890000_bib5","doi-asserted-by":"crossref","first-page":"3004","DOI":"10.3324\/haematol.2021.278762","article-title":"The RUNX1 database (RUNX1db): establishment of an expert curated RUNX1 registry and genomics database as a public resource for familial platelet disorder with myeloid malignancy","volume":"106","author":"Homan","year":"2021","journal-title":"Haematologica"},{"issue":"6372","key":"2023082419142890000_bib6","doi-asserted-by":"crossref","first-page":"eaan4672","DOI":"10.1126\/science.aan4672","article-title":"Gene therapy comes of age","volume":"359","author":"Dunbar","year":"2018","journal-title":"Science"},{"issue":"11","key":"2023082419142890000_bib7","doi-asserted-by":"crossref","first-page":"3205","DOI":"10.1016\/j.ymthe.2021.09.001","article-title":"Understanding and overcoming adverse consequences of genome editing on hematopoietic stem and progenitor cells","volume":"29","author":"Lee","year":"2021","journal-title":"Mol Ther"},{"issue":"10","key":"2023082419142890000_bib8","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1016\/j.exphem.2015.05.004","article-title":"Targeted gene correction of RUNX1 in induced pluripotent stem cells derived from familial platelet disorder with propensity to myeloid malignancy restores normal megakaryopoiesis","volume":"43","author":"Iizuka","year":"2015","journal-title":"Exp Hematol"},{"issue":"2","key":"2023082419142890000_bib9","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1182\/blood-2004-08-3280","article-title":"Loss of Runx1 perturbs adult hematopoiesis and is associated with a myeloproliferative phenotype","volume":"106","author":"Growney","year":"2005","journal-title":"Blood"},{"issue":"8","key":"2023082419142890000_bib10","doi-asserted-by":"crossref","first-page":"2015","DOI":"10.1242\/dev.129.8.2015","article-title":"Runx1 is required for zebrafish blood and vessel development and expression of a human RUNX1-CBF2T1 transgene advances a model for studies of leukemogenesis","volume":"129","author":"Kalev-Zylinska","year":"2002","journal-title":"Development"},{"issue":"11","key":"2023082419142890000_bib11","doi-asserted-by":"crossref","first-page":"2563","DOI":"10.1242\/dev.126.11.2563","article-title":"Cbfa2 is required for the formation of intra-aortic hematopoietic clusters","volume":"126","author":"North","year":"1999","journal-title":"Development"},{"issue":"12","key":"2023082419142890000_bib12","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.1182\/blood-2014-01-550525","article-title":"Targeted correction of RUNX1 mutation in FPD patient-specific induced pluripotent stem cells rescues megakaryopoietic defects","volume":"124","author":"Connelly","year":"2014","journal-title":"Blood"},{"issue":"19","key":"2023082419142890000_bib13","doi-asserted-by":"crossref","first-page":"2662","DOI":"10.1182\/blood.2020006389","article-title":"RUNX-1 haploinsufficiency causes a marked deficiency of megakaryocyte-biased hematopoietic progenitor cells","volume":"137","author":"Estevez","year":"2021","journal-title":"Blood"},{"issue":"3","key":"2023082419142890000_bib14","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1182\/bloodadvances.2020002709","article-title":"Restoring RUNX1 deficiency in RUNX1 familial platelet disorder by inhibiting its degradation","volume":"5","author":"Krutein","year":"2021","journal-title":"Blood Adv"},{"issue":"16","key":"2023082419142890000_bib15","doi-asserted-by":"crossref","first-page":"1774","DOI":"10.1182\/blood.2021014875","article-title":"Macaque clonal hematopoiesis model demonstrates expansion of TET2-disrupted clones and utility for testing interventions","volume":"140","author":"Shin","year":"2022","journal-title":"Blood"},{"issue":"15","key":"2023082419142890000_bib16","doi-asserted-by":"crossref","first-page":"2070","DOI":"10.1182\/blood-2016-10-687830","article-title":"Role of RUNX1 in hematological malignancies","volume":"129","author":"Sood","year":"2017","journal-title":"Blood"},{"issue":"6","key":"2023082419142890000_bib17","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1182\/blood-2014-06-585513","article-title":"Level of RUNX1 activity is critical for leukemic predisposition but not for thrombocytopenia","volume":"125","author":"Antony-Debr\u00e9","year":"2015","journal-title":"Blood"},{"issue":"4","key":"2023082419142890000_bib18","doi-asserted-by":"crossref","first-page":"448","DOI":"10.3324\/haematol.2015.137125","article-title":"Helicase-like transcription factor is a RUNX1 target whose downregulation promotes genomic instability and correlates with complex cytogenetic features in acute myeloid leukemia","volume":"101","author":"Cheng","year":"2016","journal-title":"Haematologica"},{"issue":"1","key":"2023082419142890000_bib19","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.ymthe.2021.06.016","article-title":"Prediction and validation of hematopoietic stem and progenitor cell off-target editing in transplanted rhesus macaques","volume":"30","author":"AlJanahi","year":"2022","journal-title":"Mol Ther"},{"issue":"4","key":"2023082419142890000_bib20","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1177\/1093526618822108","article-title":"Bone marrow morphology associated with germline RUNX1 mutations in patients with familial platelet disorder with associated myeloid malignancy","volume":"22","author":"Chisholm","year":"2019","journal-title":"Pediatr Dev Pathol"},{"issue":"4","key":"2023082419142890000_bib21","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1182\/blood.V99.4.1364","article-title":"In\u00a0vitro analyses of known and novel RUNX1\/AML1 mutations in dominant familial platelet disorder with predisposition to acute myelogenous leukemia: implications for mechanisms of pathogenesis","volume":"99","author":"Michaud","year":"2002","journal-title":"Blood"},{"issue":"12","key":"2023082419142890000_bib22","doi-asserted-by":"crossref","first-page":"4639","DOI":"10.1182\/blood-2008-05-156745","article-title":"Five new pedigrees with inherited RUNX1 mutations causing familial platelet disorder with propensity to myeloid malignancy","volume":"112","author":"Owen","year":"2008","journal-title":"Blood"},{"issue":"5","key":"2023082419142890000_bib23","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1111\/jth.12550","article-title":"Mechanisms underlying platelet function defect in a pedigree with familial platelet disorder with a predisposition to acute myelogenous leukemia: potential role for candidate RUNX 1 targets","volume":"12","author":"Glembotsky","year":"2014","journal-title":"J\u00a0Thromb Haemost"},{"issue":"12","key":"2023082419142890000_bib24","doi-asserted-by":"crossref","first-page":"4664","DOI":"10.1182\/blood-2005-01-0050","article-title":"Low Mpl receptor expression in a pedigree with familial platelet disorder with predisposition to acute myelogenous leukemia and a novel AML1 mutation","volume":"105","author":"Heller","year":"2005","journal-title":"Blood"},{"issue":"44","key":"2023082419142890000_bib25","doi-asserted-by":"crossref","first-page":"30045","DOI":"10.1074\/jbc.M804768200","article-title":"AML1\/RUNX1 works as a negative regulator of c-Mpl in hematopoietic stem cells","volume":"283","author":"Satoh","year":"2008","journal-title":"J\u00a0Biol Chem"},{"issue":"12","key":"2023082419142890000_bib26","doi-asserted-by":"crossref","first-page":"2082","DOI":"10.1002\/pbc.25668","article-title":"Analyses of genetic and clinical parameters for screening patients with inherited thrombocytopenia with small or normal-sized platelets","volume":"62","author":"Ouchi-Uchiyama","year":"2015","journal-title":"Pediatr Blood Cancer"},{"issue":"13","key":"2023082419142890000_bib27","doi-asserted-by":"crossref","first-page":"2708","DOI":"10.1182\/blood-2012-04-422337","article-title":"Dysmegakaryopoiesis of FPD\/AML pedigrees with constitutional RUNX1 mutations is linked to myosin II deregulated expression","volume":"120","author":"Bluteau","year":"2012","journal-title":"Blood"}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/141\/3\/231\/2073528\/blood_bld-2022-018193-main.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/141\/3\/231\/2073528\/blood_bld-2022-018193-main.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,24]],"date-time":"2023-08-24T19:15:10Z","timestamp":1692904510000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/141\/3\/231\/486973\/A-RUNX1-FPDMM-rhesus-macaque-model-reproduces-the"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,19]]},"references-count":27,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2023,1,19]]}},"URL":"https:\/\/doi.org\/10.1182\/blood.2022018193","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,19]]}}}