Myelodysplastic syndromes (MDS) are age-related myeloid neoplasms with increased risk of progression to acute myeloid leukemia (AML). The mechanisms of transformation of MDS to AML are poorly understood, especially in relation to the aging microenvironment. We previously established an mDia1/miR-146a double knockout (DKO) mouse model phenocopying MDS. These mice develop age-related pancytopenia with oversecretion of proinflammatory cytokines. Here, we found that most of the DKO mice underwent leukemic transformation at 12–14 months of age. These mice showed myeloblast replacement of fibrotic bone marrow and widespread leukemic infiltration. Strikingly, depletion of IL-6 in these mice largely rescued the leukemic transformation and markedly extended survival. Single-cell RNA sequencing analyses revealed that DKO leukemic mice had increased monocytic blasts that were reduced with IL-6 knockout. We further revealed that the levels of surface and soluble IL-6 receptor (IL-6R) in the bone marrow were significantly increased in high-risk MDS patients. Similarly, IL-6R was also highly expressed in older DKO mice. Blocking of IL-6 signaling significantly ameliorated AML progression in the DKO model and clonogenicity of CD34-positive cells from MDS patients. Our study establishes a mouse model of progression of age-related MDS to AML and indicates the clinical significance of targeting IL-6 signaling in treating high-risk MDS.

中文翻译：

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骨髓限制性 IL-6 信号介导骨髓增生异常综合征进展为急性髓细胞白血病

骨髓增生异常综合征 (MDS) 是与年龄相关的髓系肿瘤，其进展为急性髓系白血病 (AML) 的风险增加。MDS 转化为 AML 的机制知之甚少，尤其是与老化的微环境有关的机制。我们之前建立了一个 mDia1/miR-146a 双敲除 (DKO) 小鼠模型表型 MDS。这些小鼠出现与年龄相关的全血细胞减少症，并伴有过度分泌的促炎细胞因子。在这里，我们发现大多数 DKO 小鼠在 12-14 个月大时发生白血病转化。这些小鼠表现出纤维化骨髓的成髓细胞替代和广泛的白血病浸润。引人注目的是，这些小鼠中 IL-6 的消耗在很大程度上挽救了白血病转化并显着延长了生存期。单细胞 RNA 测序分析显示，DKO 白血病小鼠的单核细胞增加，而 IL-6 敲除则减少。我们进一步揭示了高危MDS患者骨髓中表面和可溶性IL-6受体（IL-6R）的水平显着增加。同样，IL-6R 在老年 DKO 小鼠中也高度表达。阻断 IL-6 信号通路显着改善了 DKO 模型中的 AML 进展和来自 MDS 患者的 CD34 阳性细胞的克隆形成。我们的研究建立了与年龄相关的 MDS 进展为 AML 的小鼠模型，并表明靶向 IL-6 信号传导在治疗高危 MDS 中的临床意义。我们进一步揭示了高危MDS患者骨髓中表面和可溶性IL-6受体（IL-6R）的水平显着增加。同样，IL-6R 在老年 DKO 小鼠中也高度表达。阻断 IL-6 信号通路显着改善了 DKO 模型中的 AML 进展和来自 MDS 患者的 CD34 阳性细胞的克隆形成。我们的研究建立了与年龄相关的 MDS 进展为 AML 的小鼠模型，并表明靶向 IL-6 信号传导在治疗高危 MDS 中的临床意义。我们进一步揭示了高危MDS患者骨髓中表面和可溶性IL-6受体（IL-6R）的水平显着增加。同样，IL-6R 在老年 DKO 小鼠中也高度表达。阻断 IL-6 信号通路显着改善了 DKO 模型中的 AML 进展和来自 MDS 患者的 CD34 阳性细胞的克隆形成。我们的研究建立了与年龄相关的 MDS 进展为 AML 的小鼠模型，并表明靶向 IL-6 信号传导在治疗高危 MDS 中的临床意义。