长期以来，人们一直认为常见感染在儿童 B 细胞急性淋巴细胞白血病 (B-ALL) 的发展中发挥着一定作用。然而，流行病学研究报告称，感染暴露对随后的 B-ALL 风险产生矛盾的影响，并且没有特定的病原体与该疾病明确相关。解释不同结果的统一机制可以为疾病预防策略提供信息。我们之前报道过，模式识别受体 (PRR) 配体 Poly(I:C) 对 B-ALL 细胞产生的影响与其他基于核酸的 PRR 配体观察到的影响不同。在这里，使用多个双链 RNA 部分，我们表明暴露于 Poly(I:C) 的总体结果反映了其与内体和细胞质受体连接诱导的相反反应的平衡。这种 PRR 反应生物学是小鼠和人类 B-ALL 共有的，并且主要通过 TNF-α 信号传导，在 B-ALL 白血病前期阶段增加体内白血病起始细胞负担。在小鼠和人类环境中，反应免疫系统的年龄进一步影响 dsRNA 暴露对 B-ALL 细胞的影响。总体而言，我们的研究表明，潜在的促白血病和抗白血病作用均可以通过刺激病原体识别途径而产生，并为感染暴露和 B-ALL 所报告的流行病学关联的对比提供了机械解释。版权所有 © 2023 美国血液学会。

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.Copyright © 2023 American Society of Hematology.