Bone marrow-confined IL-6 signaling mediates the progression of myelodysplastic syndromes to acute myeloid leukemia.
Bone marrow-confined IL-6 signaling mediates the progression of myelodysplastic syndromes to acute myeloid leukemia.
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DOI：
10.1172/jci152673
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发表时间：
2022-09-01
影响因子：
15.9
通讯作者：
Ji, Peng
中科院分区：
文献类型：
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作者：
Mei, Yang;Ren, Kehan;Liu, Yijie;Ma, Annabel;Xia, Zongjun;Han, Xu;Li, Ermin;Tariq, Hamza;Bao, Haiyan;Xie, Xinshu;Zou, Cheng;Zhang, Dingxiao;Li, Zhaofeng;Dong, Lili;Verma, Amit;Lu, Xinyan;Abaza, Yasmin;Altman, Jessica K.;Sukhanova, Madina;Yang, Jing;Ji, Peng
骨髓增生异常综合征(MDS)是与年龄相关的髓系肿瘤，进展为急性髓系白血病(AML)的风险增加。MDS向AML转化的机制尚不清楚，尤其是与衰老的微环境有关。我们以前建立了mDia1/miR-146a双基因敲除(DKO)小鼠的MDS表型复制模型。这些小鼠出现与年龄相关的全血细胞减少症，并伴有促炎细胞因子的过度分泌。在这里，我们发现大多数DKO小鼠在12-14个月龄时经历了白血病转化。这些小鼠表现为成髓细胞替代纤维化的骨髓和广泛的白血病浸润性病变。引人注目的是，这些小鼠体内IL-6的耗尽在很大程度上挽救了白血病的转化，并显著延长了存活期。单细胞RNA测序分析显示，DKO白血病小鼠的单核细胞母细胞增加，而IL-6基因敲除后则减少。进一步揭示高危MDS患者骨髓表面和可溶性IL-6受体(IL-6R)水平显著升高。同样，IL-6R在老年DKO小鼠中也高度表达。阻断IL-6信号显著改善DKO模型的AML进展和MDS患者CD34阳性细胞的克隆性。我们的研究建立了年龄相关性MDS向AML进展的小鼠模型，并指出了靶向IL-6信号转导在治疗高危MDS中的临床意义。
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.