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KMT2A::MLLT3 is among the most common translocations initiating leukaemia in infants, where it can manifest with a myeloid or lymphoid leukaemia phenotype. The cell-of-origin and the mechanisms driving lineage choice in KMT2A::MLLT3+ infant leukaemia are poorly understood. In this study, we show that a subset of foetal lymphoid-primed multipotent progenitors (LMPPs) expressing the Colony-Stimulating Factor 1 receptor (CSF1R) gives rise to acute myeloid leukaemia (AML) upon KMT2A::MLLT3 induction in a mouse model, with the myeloid phenotype, at least in part, being dependent on CSF1R signalling. In line with their leukaemia-propagating properties, KMT2A::MLLT3\u2009+\u2009CSF1R+ LMPPs possess a stem\u00a0cell-like and myeloid-biased expression signature and require autophagy to expand and form blast-like colonies in methylcellulose. Interrogation of public datasets confirms the existence of a human foetal-restricted CSF1R+\u2009LMPP population at early stages of embryonic development. Finally, CSF1R inhibition on a KMT2A::MLLT3+ paediatric leukaemia cell line resulted in significant cell death, suggesting that CSF1R could be therapeutically targeted in these patients. Our findings suggest that KMT2A::MLLT3+ infant AML may originate from foetal liver CSF1R+ LMPPs, and that these patients may benefit from anti-CSF1R-CAR-T cell therapy.<\/jats:p>","DOI":"10.1038\/s41375-025-02856-4","type":"journal-article","created":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T07:12:23Z","timestamp":1768547543000},"page":"540-552","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CSF1R marks a subset of foetal haematopoietic multipotent progenitor cells with acute myeloid leukaemia propagation properties"],"prefix":"10.1038","volume":"40","author":[{"given":"Giuseppina","family":"Camiolo","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Gonz\u00e1lez Silvera","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tom","family":"Leah","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8616-0096","authenticated-orcid":false,"given":"J\u00fcrg","family":"Schwaller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6880-4895","authenticated-orcid":false,"given":"Katrin","family":"Ottersbach","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,1,16]]},"reference":[{"key":"2856_CR1","doi-asserted-by":"publisher","first-page":"1817","DOI":"10.1002\/cam4.1122","volume":"6","author":"AS Alfaar","year":"2017","unstructured":"Alfaar AS, Hassan WM, Bakry MS, Qaddoumi I. 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