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The fusion originates <jats:italic>in utero<\/jats:italic>, yet the embryonic initiating steps of disease development remain poorly understood. Here, we present a novel murine <jats:italic>KMT2A::AFF1<\/jats:italic> model, that provides key insights into <jats:italic>KMT2A::AFF1<\/jats:italic> pre-leukemia, relevant to human disease. The model enables precise oncogene induction, and upon targeting hematopoietic stem and progenitor cells (HSPCs) a selective negative impact on proliferation of hematopoietic stem cells (HSCs) was observed, regardless of developmental state during induction. However, a unique CD24<jats:sup>+<\/jats:sup>PreProB subset expanded exclusively within the <jats:italic>KMT2A::AFF1<\/jats:italic> embryonic context. This population was absent when targeting lymphoid progenitors, highlighting the importance of the cell of origin for leukemic development. The CD24<jats:sup>+<\/jats:sup>PreProB subset displayed key features of pre-leukemic stem cells, including lineage plasticity and aberrant engraftment ability. In line with their pre-malignant phenotype, single-cell transcriptomics revealed a signature consistent with stemness, and notable, up-regulation of <jats:italic>Hmga2<\/jats:italic>, a regulator of self-renewal. The signature was critically transferable to human KMT2A::AFF1 patients. Furthermore, given that CD24 is a potential therapeutic target, our findings uncover a distinct embryonic pre-leukemic state with direct relevance to human disease.<\/jats:p>","DOI":"10.1038\/s41375-025-02665-9","type":"journal-article","created":{"date-parts":[[2025,7,11]],"date-time":"2025-07-11T07:50:38Z","timestamp":1752220238000},"page":"2099-2111","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Ontogeny-specific induction of the KMT2A::AFF1-fusion drives development of a distinct CD24 positive pre-leukemic state"],"prefix":"10.1038","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6271-6256","authenticated-orcid":false,"given":"Ariana S.","family":"Caldero\u0301n","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roshanak","family":"Ghazanfari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zahra","family":"Masoumi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shabnam","family":"Kharazi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Palo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0854-2328","authenticated-orcid":false,"given":"Stefan","family":"Lang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristijonas","family":"\u017demaitis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8636-2189","authenticated-orcid":false,"given":"Mohamed","family":"Eldeeb","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3966-3875","authenticated-orcid":false,"given":"Agatheeswaran","family":"Subramaniam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shamit","family":"Soneji","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4986-1656","authenticated-orcid":false,"given":"Ronald W.","family":"Stam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8761-4237","authenticated-orcid":false,"given":"David","family":"Bryder","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4876-1218","authenticated-orcid":false,"given":"Charlotta","family":"B\u00f6iers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,7,11]]},"reference":[{"key":"2665_CR1","doi-asserted-by":"publisher","first-page":"2246","DOI":"10.1200\/JCO.19.00261","volume":"37","author":"R Pieters","year":"2019","unstructured":"Pieters R, De Lorenzo P, Ancliffe P, Aversa LA, Brethon B, Biondi A, et al. 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Current affiliation for Shabnam Kharazi is NextCell Pharrma AB, Huddinge, Sweden, for Mohamed Eldeeb Acrivon Therapeutics, Lund, Sweden and for Zahra Masoumi Department of Biology, University of York, York, United Kingdom.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}