The initial steps of B-cell acute lymphoblastic leukemia (B-ALL) development usually pass unnoticed in children. Several preclinical studies have shown that exposure to immune stressors triggers the transformation of preleukemic B cells to full-blown B-ALL, but how this takes place is still a longstanding and unsolved challenge. Here we show that dysregulation of innate immunity plays a driving role in the clonal evolution of pre-malignantPax5^+/−B-cell precursors toward leukemia. Transcriptional profiling reveals thatMyd88is downregulated in immune-stressed pre-malignant B-cell precursors and in leukemic cells. Genetic reduction ofMyd88expression leads to a significant increase in leukemia incidence inPax5^+/−Myd88^+/−mice through an inflammation-dependent mechanism. Early induction of Myd88-independent Toll-like receptor 3 signaling results in a significant delay of leukemia development inPax5^+/−mice. Altogether, these findings identify a role for innate immunity dysregulation in leukemia, with important implications for understanding and therapeutic targeting of the preleukemic state in children.

Preventing development of childhood B-cell acute lymphoblastic leukemia (B-ALL), a disease with devastating effects, is a longstanding and unsolved challenge. Heterozygous germline alterations in the PAX5 gene can lead to B-ALL upon accumulation of secondary mutations affecting the JAK/STAT signaling pathway. Preclinical studies have shown that this malignant transformation occurs only under immune stress such as exposure to infectious pathogens. Here we show in Pax5+/− mice that transient, early-life administration of clinically relevant doses of ruxolitinib, a JAK1/2 inhibitor, significantly mitigates the risk of B-ALL following exposure to infection; 1 of 29 animals treated with ruxolitinib developed B-ALL versus 8 of 34 untreated mice. Ruxolitinib treatment preferentially targeted Pax5+/− versus wild-type B-cell progenitors and exerted unique effects on the Pax5+/− B-cell progenitor transcriptional program. These findings provide the first in vivo evidence for a potential strategy to prevent B-ALL development. Significance: JAK/STAT inhibition suppresses tumorigenesis in a B-ALL–susceptible mouse model, presenting a novel approach to prevent B-ALL onset.