CSF1R marks a subset of foetal haematopoietic multipotent progenitor cells with acute myeloid leukaemia propagation properties

KMT2A-rearranged infant leukaemia is one of the most severe malignancies in infants and children, and is characterised by a very aggressive phenotype and lineage plasticity. 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 + CSF1R+ LMPPs possess a stem cell-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+ LMPP 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.