Decreased levels of IL-10 accelerate development of B-cell disease in the E6R1⁺Cdkn2a^−/− model. Survival curves for cancer (A) and leukemia/lymphoma development (B) in E6R1⁺Cdkn2a^−/−Il10^+/+ mice and E6R1⁺Cdkn2a^−/−Il10^−/− mice. Log-rank (Mantel-Cox) test. (C) Number of total or nonsynonymous SNVs in B-cell leukemia/lymphomas from exome sequencing of 9 E6R1⁺Cdkn2a^−/−Il10^+/+ mice and 8 E6R1⁺Cdkn2a^−/−Il10^−/− mice. Error bars represent the mean ± standard deviation. (D) Mutation spectrum representing the frequency of mutations in each context of 96 possible trinucleotide contexts in sequenced E6R1⁺Cdkn2a^−/−Il10^+/+ and E6R1⁺Cdkn2a^−/−Il10^−/− B-cell leukemia/lymphomas. (E) Model for the role of microbial dysbiosis in childhood B-cell leukemia/lymphoma. IL-10 deficiency induces microbial dysbiosis in the gut, resulting in inflammation with distal effects of B-cell deficiency and B-cell DNA damage in the bone marrow. The inflammation-associated acquisition of genetic lesions in bone marrow B cells leads to the development of B-cell leukemia/lymphoma. Antibiotics may counteract the impact of low IL-10 by restoring bacterial homeostasis in the gut.