UCSF

Excessive inflammatory responses to common childhood infections are associated with an increased risk of pediatric B cell Acute Lymphoblastic Leukemia (B ALL). Despite the identification of several neonatal inflammatory markers as B ALL risk factors, the mechanism(s) by which these markers stimulate an excessive immune response leading B ALL remain largely unknown. Here, we demonstrate that IL 10 deficiency, a neonatal risk factor for B ALL, indirectly impairs B lymphopoiesis and increases B cell DNA damage through induction of inflammation in mice. Altered B cell number and DNA damage in Il10-/- mice were associated with a module of 6 pro inflammatory/myeloid associated cytokines (IL-1, IL-6, IL-12p40, IL 13, CCL4/MIP 1, and G CSF). Importantly, inflammation and defects in bone marrow B cells were attenuated by treating pre leukemic Il10-/- Ckdn2a-/- mice with antibiotics that target Helicobacter species. In the TEL AML1 Ckdn2a-/- mouse model of B ALL, decreased levels of IL-10 accelerated B cell neoplasms in a dose dependent manner, and altered the mutational profile of B cell neoplasm to favor C>T and T>C mutations. Infection of Cdkn2a-/- mice to Aspiculuris, a parasite that induces IL-10 production, delayed the development of B cell neoplasms in Cdkn2a / mice, demonstrating a novel protective effect of microbial exposure. Our results identify commensal bacteria as modulators of bone marrow B cell responses to IL 10 deficiency, and suggest that microbial dysbiosis underlies the infectious etiology of pediatric B ALL.