Infection Exposure Promotes Precursor B-cell Leukemia via Impaired H3K4 Demethylases.

is associated with the most common subtype of childhood leukemia. As few carriers develop precursor B-cell acute lymphocytic leukemia (pB-ALL), the underlying genetic basis for development of full-blown leukemia remains to be identified, but the appearance of leukemia cases in time-space clusters keeps infection as a potential causal factor. Here, we present genetic evidence mechanistically connecting preleukemic expression in hematopoetic stem cells/precursor cells (HSC/PC) and postnatal infections for human-like pB-ALL. In our model, conferred a low risk of developing pB-ALL after exposure to common pathogens, corroborating the low incidence observed in humans. Murine preleukemic pro/preB cells showed high expression, known for human pB-ALL. Murine and human pB-ALL revealed recurrent genomic alterations, with a relevant proportion affecting genes of the lysine demethylase () family. KDM5C loss of function resulted in increased levels of H3K4me3, which coprecipitated with RAG2 in a human cell line model, laying the molecular basis for recombination activity. We conclude that alterations of KDM family members represent a disease-driving mechanism and an explanation for RAG off-target cleavage observed in humans. Our results explain the genetic basis for clonal evolution of an preleukemic clone to pB-ALL after infection exposure and offer the possibility of novel therapeutic approaches. .