Differential Effects of Pathogenic and Non-Pathogenic Early-Life Exposures on Acute Lymphoblastic Leukemia Progression in Eμ-RET Mice

Abstract B cell precursor acute lymphoblastic leukemia (B-ALL), the most common cancer in children, is a multi-step disease that is initiated in utero; although B-ALL has an incidence peak at 3-5 years of age, the majority of these children have pre-leukemic cells detectable at birth. Notably, however, up to 5% of newborns have detectable leukemia-initiating genetic abnormalities in their blood, but most of these infants go on to live healthy lives. Identifying the mechanisms that inhibit or drive B-ALL progression has the potential to inform new therapeutic or preventative strategies. Infection has been identified as a potential leukemia progression modifier to explain the discordance between the number of children with pre-leukemia and the number who develop B-ALL. While epidemiological studies have identified the timing of infection as a critical variable, the mechanisms underlying this association remain unknown. The early incidence peak is dominated by the ETV6-RUNX1 translocation-positive and high hyperdiploid subgroups, which together account for ~50% of pediatric B-ALL cases. We have previously reported the ability of immune stimulation with infection-associated toll-like receptor agonists to reduce pre-leukemic cell burden and delay leukemia onset in Eμ-RET mice, in which hyperdiploid B-ALL is fully penetrant. Furthermore, exposure of Eμ-RET mice to mild infections with Listeria monocytogenes (Lm), Murine herpesvirus 68 (MHV) or Murine cytomegalovirus (MCMV) induces a profound, age-dependent depletion of pre-leukemia cells, with neonatal mice, but not adults, exhibiting reduced leukemia progression after infection. Here, we extend this work by evaluating the influence of Saccharomyces cerevisiae (Sc) on leukemia development, hypothesizing that exposures to non-pathogenic commensal organisms would induce a similar protective immune activity. Using our established methodology, Eμ-RET mice were exposed to pathogenic or non-pathogenic organisms at six days of age by intraperitoneal injection (Lm, MCMV, Sc) or intranasally (MHV), and evaluated for pre-leukemic cell burden eight days later. In contrast to the response to pathogens, exposure of neonates to Sc did not result in a reduction of pre-leukemic cell numbers, even after inoculation with significantly higher numbers of yeast particles. The depletion of pre-leukemia cells induced by infection with pathogenic organisms was dependent on the presence of both γδ T cells and NK cells, with the latter population exerting direct cytotoxicity against B-ALL cells. Consistent with a failure to induce pre-leukemia depletion, Sc exposure achieved significantly less activation of γδ T cells and did not activate NK cells at all in neonatal Eμ-RET mice. Overall, our results reveal the primacy of the γδ T/NK cell response axis for the depletion of pre-leukemic cells after early-life infection and thus identify a novel immune response pathway with the potential to prevent ALL progression in children. Furthermore, these data indicate that not all age-associated exposures are capable of driving an immune response that reduces the risk of leukemia, with the dietary commensal Saccharomyces cerevisiae failing to generate a protective response in neonatal mice. This study significantly enhances our mechanistic understanding of immune-mediated modification of B-ALL progression. Disclosures No relevant conflicts of interest to declare.

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