Age and ligand specificity influence the outcome of pathogen engagement on preleukemic and leukemic B-cell precursor populations

Abstract

Common infections have long been proposed to play a role in the development of pediatric B cell acute lymphoblastic leukemia (B-ALL). However, epidemiological studies report contradictory effects of infection exposure on subsequent B-ALL risk, and no specific pathogen has been definitively linked to the disease. A unifying mechanism to explain the divergent outcomes could inform disease prevention strategies. We previously reported that the pattern recognition receptor (PRR) ligand Poly(I:C) exerted effects on B-ALL cells that were distinct from those observed with other nucleic acid-based PRR ligands. Here, using multiple double-stranded RNA moieties, we show that the overall outcome of exposure to Poly(I:C) reflects the balance of opposing responses induced by its ligation to endosomal and cytoplasmic receptors. This PRR response biology is shared between mouse and human B-ALL and increases leukemia-initiating cell burden in vivo during the preleukemia phase of B-ALL, primarily through TNF-alpha signaling. The age of the responding immune system further influences the impact of dsRNA exposure on B-ALL cells in both mouse and human settings. Overall, our study demonstrates that potentially pro- and anti-leukemic effects can each be generated by stimulation of pathogen recognition pathways and indicates a mechanistic explanation for the contrasting epidemiologic associations reported for infection exposure and B-ALL.