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Cellular and\/or animal models are helpful to uncovering the role of a variant in disease progression. Twenty-five mice per genotype (RUNX1WT\/WT, RUNX1WT\/L43S, RUNX1L43S\/L43S), previously generated by CRISPR\/Cas9, and nine sub-lethally irradiated mice per genotype were investigated. Peripheral blood (PB), bone marrow (BM), and spleen samples were analyzed by flow cytometry and histopathology. Deregulated genes were analyzed by RNA-seq in BM. An aberrant myeloid Mac1+Sca1+ckit\u2212 population in the PB, BM, and spleen of two homozygous and one heterozygous mouse was observed, as well as BM hypercellularity. No Mac1+Sca1+ckit\u2212 cells were detected in any RUNX1WT\/WT mice. Moreover, the spleen of both homozygous mice showed destruction of the white\/red pulp and the presence of apoptotic cells. The aberrant population was also detected in four irradiated mice, two heterozygous and two homozygous, in their PB, BM, and spleen. RNA-seq studies showed 698 genes significantly deregulated in the three non-irradiated Mac1+Sca1+ckit\u2212 mice vs. six healthy mice, highlighting the alteration of genes involved in apoptosis and DNA repair. These results indicate that the homozygous form of the variant p.Leu43Ser may contribute to the pathogenesis of aberrant cells.<\/jats:p>","DOI":"10.3390\/biom15050708","type":"journal-article","created":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T03:59:26Z","timestamp":1747108766000},"page":"708","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Examining the Effects of the RUNX1 p.Leu43Ser Variant on FPD\/AML Phenotypes Using a CRISPR\/Cas9-Generated Knock-In Murine Model"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2005-1919","authenticated-orcid":false,"given":"Ana","family":"Marin-Quilez","sequence":"first","affiliation":[{"name":"Cancer Research Center-CSIC, Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca (IBSAL), University of Salamanca, 37007 Salamanca, Spain"},{"name":"Servicio de Hematolog\u00eda y Oncolog\u00eda M\u00e9dica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonaci\u00f3n, University of Murcia, IMIB-Pascual Parrilla, CIBERER-U765, 30003 Murcia, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4758-2151","authenticated-orcid":false,"given":"Ignacio","family":"Garc\u00eda-Tu\u00f1\u00f3n","sequence":"additional","affiliation":[{"name":"Cancer Research Center-CSIC, Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca (IBSAL), University of Salamanca, 37007 Salamanca, Spain"},{"name":"Departament of Biomedicine and Biotecnology, Universidad de Alcal\u00e1, 28801 Alcal\u00e1 de Henares, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9781-4198","authenticated-orcid":false,"given":"Roc\u00edo","family":"Benito","sequence":"additional","affiliation":[{"name":"Cancer Research Center-CSIC, Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca (IBSAL), University of Salamanca, 37007 Salamanca, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3791-4215","authenticated-orcid":false,"given":"Jos\u00e9 Luis","family":"Ordo\u00f1ez","sequence":"additional","affiliation":[{"name":"Cancer Research Center-CSIC, Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca (IBSAL), University of Salamanca, 37007 Salamanca, Spain"},{"name":"Laboratory of Pharmacology, Department of Physiology and Pharmacology, Faculty of Pharmacy, University of Salamanca, 37007 Salamanca, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0716-385X","authenticated-orcid":false,"given":"Lorena","family":"D\u00edaz-Ajenjo","sequence":"additional","affiliation":[{"name":"Cancer Research Center-CSIC, Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca (IBSAL), University of Salamanca, 37007 Salamanca, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0290-6825","authenticated-orcid":false,"given":"Ana","family":"Lama-Villanueva","sequence":"additional","affiliation":[{"name":"Cancer Research Center-CSIC, Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca (IBSAL), University of Salamanca, 37007 Salamanca, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8747-6831","authenticated-orcid":false,"given":"Carmen","family":"Guerrero","sequence":"additional","affiliation":[{"name":"Cancer Research Center-CSIC, Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca (IBSAL), University of Salamanca, 37007 Salamanca, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2400-624X","authenticated-orcid":false,"given":"Jes\u00fas","family":"P\u00e9rez-Losada","sequence":"additional","affiliation":[{"name":"Cancer Research Center-CSIC, Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca (IBSAL), University of Salamanca, 37007 Salamanca, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3266-7996","authenticated-orcid":false,"given":"Jos\u00e9 Ram\u00f3n","family":"Gonz\u00e1lez-Porras","sequence":"additional","affiliation":[{"name":"Department of Hematology, Complejo Asistencial Universitario de Salamanca (CAUSA), Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca (IBSAL), Universidad de Salamanca (USAL), 37007 Salamanca, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9661-9371","authenticated-orcid":false,"given":"Jes\u00fas Mar\u00eda","family":"Hern\u00e1ndez-Rivas","sequence":"additional","affiliation":[{"name":"Cancer Research Center-CSIC, Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca (IBSAL), University of Salamanca, 37007 Salamanca, Spain"},{"name":"Department of Hematology, Complejo Asistencial Universitario de Salamanca (CAUSA), Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca (IBSAL), Universidad de Salamanca (USAL), 37007 Salamanca, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1048-8148","authenticated-orcid":false,"given":"M\u00f3nica","family":"del Rey","sequence":"additional","affiliation":[{"name":"Cancer Research Center-CSIC, Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca (IBSAL), University of Salamanca, 37007 Salamanca, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8007-3909","authenticated-orcid":false,"given":"Jos\u00e9 Mar\u00eda","family":"Bastida","sequence":"additional","affiliation":[{"name":"Department of Hematology, Complejo Asistencial Universitario de Salamanca (CAUSA), Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca (IBSAL), Universidad de Salamanca (USAL), 37007 Salamanca, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,12]]},"reference":[{"key":"ref_1","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"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Bellissimo, D.C., and Speck, N.A. (2017). RUNX1 Mutations in Inherited and Sporadic Leukemia. Front. Cell Dev. 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Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1038\/leu.2016.364","article-title":"Preleukemia: One name, many meanings","volume":"31","author":"Koeffler","year":"2017","journal-title":"Leukemia"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e70057","DOI":"10.1002\/hem3.70057","article-title":"Disease characteristics and outcome of acute myeloid leukemia in familial platelet disorder with associated myeloid malignancy","volume":"9","author":"Ernst","year":"2025","journal-title":"Hemasphere"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5583","DOI":"10.1182\/blood-2008-07-168260","article-title":"High frequency of RUNX1 biallelic alteration in acute myeloid leukemia secondary to familial platelet disorder","volume":"113","author":"Preudhomme","year":"2009","journal-title":"Blood"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1038\/leu.2015.236","article-title":"Somatic mutations associated with leukemic progression of familial platelet disorder with predisposition to acute myeloid leukemia","volume":"30","author":"Duployez","year":"2016","journal-title":"Leukemia"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2962","DOI":"10.1182\/bloodadvances.2019000644","article-title":"ClinGen Myeloid Malignancy Variant Curation Expert Panel recommendations for germline RUNX1 variants","volume":"3","author":"Luo","year":"2019","journal-title":"Blood Adv."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"870","DOI":"10.3324\/haematol.2018.214221","article-title":"How I curate: Applying American Society of Hematology-Clinical Genome Resource Myeloid Malignancy Variant Curation Expert Panel rules for RUNX1 variant curation for germline predisposition to myeloid malignancies","volume":"105","author":"Wu","year":"2020","journal-title":"Haematologica"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1080\/10428194.2019.1675882","article-title":"Controversies about germline RUNX1 missense variants","volume":"61","author":"Duployez","year":"2020","journal-title":"Leuk. Lymphoma"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3304","DOI":"10.1038\/s41375-021-01200-w","article-title":"Functional classification of RUNX1 variants in familial platelet disorder with associated myeloid malignancies","volume":"35","author":"Decker","year":"2021","journal-title":"Leukemia"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1458","DOI":"10.1016\/j.stemcr.2021.04.013","article-title":"Study of inherited thrombocytopenia resulting from mutations in ETV6 or RUNX1 using a human pluripotent stem cell model","volume":"16","author":"Borst","year":"2021","journal-title":"Stem Cell Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"101603","DOI":"10.1016\/j.scr.2019.101603","article-title":"GENYOi005-A: An induced pluripotent stem cells (iPSCs) line generated from a patient with Familial Platelet Disorder with associated Myeloid Malignancy (FPDMM) carrying a p.Thr196Ala variant","volume":"41","author":"Lamolda","year":"2019","journal-title":"Stem Cell Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.1016\/j.jtha.2023.01.023","article-title":"Platelet transcriptome analysis in patients with germline RUNX1 mutations","volume":"21","author":"Bastida","year":"2023","journal-title":"J. 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