ETV6‐RUNX1 (E/R) fusion gene, arising in utero from translocation t(12;21)(p13:q22), is the most frequent alteration in childhood acute lymphoblastic leukemia (ALL). However, E/R is insufficient to cause overt leukemia since it generates a clinically silent pre‐leukemic clone which persists in the bone marrow but fails to out‐compete normal progenitors. Conversely, pre‐leukemic cells show increased susceptibility to transformation following additional genetic insults. Infections/inflammation are the most accredited triggers for mutations accumulation and leukemic transformation in E/R⁺ pre‐leukemic cells. However, precisely how E/R and inflammation interact in promoting leukemia is still poorly understood. Here we demonstrate that IL6/TNFα/ILβ pro‐inflammatory cytokines cooperate with BM‐MSC in promoting the emergence of E/R⁺ Ba/F3 over their normal counterparts by differentially affecting their proliferation and survival. Moreover, IL6/TNFα/ILβ‐stimulated BM‐MSC strongly attract E/R⁺ Ba/F3 in a CXCR2‐dependent manner. Interestingly, E/R‐expressing human CD34⁺IL7R⁺ progenitors, a putative population for leukemia initiation during development, were preserved in the presence of BM‐MSC and IL6/TNFα/ILβ compared to their normal counterparts. Finally, the extent of DNA damage increases within the inflamed niche in both control and E/R‐expressing Ba/F3, potentially leading to transformation in the apoptosis‐resistant pre‐leukemic clone. Overall, our data provide new mechanistic insights into childhood ALL pathogenesis.

中文翻译：

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促炎细胞因子有利于间充质利基模型中ETV6-RUNX1阳性的白血病前细胞的出现。

ETV6-RUNX1（E / R）融合基因是由易位t（12; 21）（p13：q22）在子宫内产生的，是儿童急性淋巴细胞白血病（ALL）中最常见的改变。但是，E / R不足以引起明显的白血病，因为它会产生临床上沉默的白血病前克隆，该克隆在骨髓中持续存在，但不能胜过正常祖细胞。相反，白血病患者的细胞在进行额外的遗传损伤后显示出对转化的敏感性增加。感染/炎症是E / R ^+中突变积累和白血病转化最认可的诱因白血病前细胞。但是，对于E / R和炎症在促进白血病中如何相互作用的确切了解仍然很少。在这里，我们证明IL6 /TNFα/ILβ促炎细胞因子与BM-MSC协同作用，通过差异地影响其增殖和存活来促进E / R ⁺ Ba / F3的出现。此外，IL6 /TNFα/ILβ刺激的BM-MSC以依赖CXCR2的方式强烈吸引E / R ⁺ Ba / F3。有趣的是，表达E / R的人类CD34 ⁺ IL7R ⁺与正常人相比，在存在BM-MSC和IL6 /TNFα/ILβ的情况下，保留了祖细胞，这是在发育过程中引发白血病的假定人群。最后，在对照和表达E / R的Ba / F3中发炎的生态位内，DNA损伤的程度都会增加，可能导致抗凋亡前白血病克隆的转化。总体而言，我们的数据为儿童ALL发病机理提供了新的机理见解。