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Decreased IL-10 accelerates B-cell leukemia/lymphoma in a mouse model of pediatric lymphoid leukemia


Exposures to a wide repertoire of common childhood infections and strong inflammatory responses to those infections are associated with the risk of pediatric B-cell acute lymphoblastic leukemia (B-ALL) in opposing directions. Neonatal inflammatory markers are also related to risk by unknown mechanism(s). Here, we demonstrate that interleukin-10 (IL-10) deficiency, which is associated with childhood B-ALL, indirectly impairs B lymphopoiesis and increases B-cell DNA damage in association with a module of 6 proinflammatory/myeloid-associated cytokines (IL-1α, IL-6, IL-12p40, IL-13, macrophage inflammatory protein-1β/CCL4, and granulocyte colony-stimulating factor). Importantly, antibiotics attenuated inflammation and B-cell defects in preleukemic Cdkn2a-/-Il10-/- mice. In an ETV6-RUNX1+ (E6R1+) Cdkn2a-/- 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 these neoplasms. Our results illuminate a mechanism through which a low level of IL-10 can create a risk for leukemic transformation and support developing evidence that microbial dysbiosis contributes to pediatric B-ALL.

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