Ontogenic changes in hematopoietic hierarchy determine pediatric specificity and disease phenotype in fusion oncogene-driven myeloid leukemia - scRNAseq - 2

Paediatric cancers present specific genetic alterations, however the principles underlying their differences to adult cancers are yet unclear. Poor prognosis paediatric myeloid leukaemia fusion oncogenes represent clinically-relevant models to investigate age-specific tumorigenesis. Here, we established an inducible murine model to show that the ETO2-GLIS2 fusion induces both megakaryoblastic and myeloid leukaemia in a cellular and developmental stage-dependent manner, reproducing different age and phenotype associations observed in patients. The aggressive megakaryoblastic leukemia phenotype developed from haematopoietic stem cells and was associated with massive rewiring of master transcription factors activities (e.g. ERG, GATA and CEBPA). Switching off ETO2-GLIS2 expression in transformed cells restored some long-term haematopoietic stem cell potential. In contrast, targeting downstream progenitors was required for the myeloid phenotype. These data demonstrate that the promiscuity between HSC and megakaryocytic states and the ontogenic changes in the cellular architecture of the hematopoietic tissue controls paediatric and phenotype specificities in myeloid leukaemia.