Age and ligand specificity influence the outcome of pathogen engagement on preleukemic and leukemic B-cell precursor populations.
Age and ligand specificity influence the outcome of pathogen engagement on preleukemic and leukemic B-cell precursor populations.
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年龄和配体特异性影响病原体参与的结果对peleukemic和白血病B细胞前体人群。
DOI：
10.1182/bloodadvances.2023010782
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发表时间：
2023-11-28
期刊：
影响因子：
7.5
通讯作者：
Reid, Gregor S. D.
中科院分区：
文献类型：
--
作者：
Atre, Tanmaya;Farrokhi, Ali;Jo, Sumin;Salitra, Samuel;Duque-Afonso, Jesus;Cleary, Michael L.;Rolf, Nina;Reid, Gregor S. D.
暴露时的年龄影响PRR参与的结果，并且这种生物学在小鼠和人B-ALL之间共享。致病性双链RNA与TLR 3的结合诱导早期肿瘤坏死因子α依赖性白血病前细胞增殖。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）的发展中起作用。然而，流行病学研究报告了感染暴露对随后的B-ALL风险的相互矛盾的影响，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战略提供信息。我们以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配体所观察到的不同。在这里，使用多个双链RNA（dsRNA）部分，我们表明，暴露于聚（I：C）的总体结果反映了其连接到内体和细胞质受体诱导的相反反应的平衡。这种PRR反应生物学在小鼠和人B-ALL之间共享，并且可以在B-ALL的白血病前期增加体内白血病起始细胞负荷，主要通过肿瘤坏死因子α信号传导。在小鼠和人类环境中，应答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可以分别通过刺激病原体识别途径产生，并表明了对感染暴露和B-ALL报告的对比流行病学关联的机制解释。
Age at the time of exposure influences the outcome of PRR engagement, and this biology is shared between mouse and human B-ALL. TLR3 engagement by pathogenic dsRNA induces tumor necrosis factor α–dependent preleukemia cell proliferation in early life. Common infections have long been proposed to play a role in the development of pediatric B-cell acute lymphoblastic leukemia (B-ALL). However, epidemiologic 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 (dsRNA) 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 can increase leukemia-initiating cell burden in vivo during the preleukemia phase of B-ALL, primarily through tumor necrosis factor α 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 proleukemic and antileukemic effects can each be generated by the stimulation of pathogen recognition pathways and indicates a mechanistic explanation for the contrasting epidemiologic associations reported for infection exposure and B-ALL.
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影响因子：
11.4
作者：
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通讯作者：
Ford A
影响因子：
64.8
作者：
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作者：
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作者：
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影响因子：
8.8
作者：
Cardwell CR;McKinney PA;Patterson CC;Murray LJ
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