To investigate whether ontogeny-related features determine the pediatric specificity in juvenile myelomonocytic leukemia (JMML), we compared the gene expression profile of hematopoietic progenitor cells sorted from JMML to their healthy counterparts isolated at different stages of ontogeny. Two groups of JMML were identified. The JMML in the first group had a fetal-like expression profile. Their progenitors showed a stronger monocytic identity than other JMML or healthy postnatal progenitors with overexpression of monocytic/dendritic, inflammasome and innate immunity markers, reminiscent of the monocyte-biased myelopoiesis characterizing physiologic fetal hematopoiesis. The second group, although clustering apart from healthy prenatal and post-natal fractions, was characterized by aberrant expression of the master oncofetal regulator LIN28B, suggesting developmental dysregulation. LIN28B expression was associated with DNA hypermethylation. Analysis of a large cohort of 108 patients with JMML showed that a high LIN28 expression was correlated to a poor outcome. Our findings highlight a strong but complex link between JMML and development, and will be important to guide future treatment strategies in this rare but severe leukemia.

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