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Bone marrow–confined IL-6 signaling mediates the progression of myelodysplastic syndromes to acute myeloid leukemia
Yang Mei, … , Jing Yang, Peng Ji
Yang Mei, … , Jing Yang, Peng Ji
Published July 28, 2022
Citation Information: J Clin Invest. 2022;132(17):e152673. https://doi.org/10.1172/JCI152673.
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Research Article Hematology Inflammation Article has an altmetric score of 42

Bone marrow–confined IL-6 signaling mediates the progression of myelodysplastic syndromes to acute myeloid leukemia

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Abstract

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.

Authors

Yang Mei, Kehan Ren, Yijie Liu, Annabel Ma, Zongjun Xia, Xu Han, Ermin Li, Hamza Tariq, Haiyan Bao, Xinshu Xie, Cheng Zou, Dingxiao Zhang, Zhaofeng Li, Lili Dong, Amit Verma, Xinyan Lu, Yasmin Abaza, Jessica K. Altman, Madina Sukhanova, Jing Yang, Peng Ji

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Figure 3

IL-6 deficiency ameliorates the defective hematopoiesis and leukemogenesis in DKO mice.

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IL-6 deficiency ameliorates the defective hematopoiesis and leukemogenes...
(A) The percentages of indicated cells among the peripheral blood mononuclear cells of the indicated mice at 12–14 months of age. TWT, n = 12; IL-6 KO, n = 8; DKO, n = 10; TKO, n = 10. Gran, granulocytes, Ly6G+CD11b+; MO, monocytes, Ly6C+CD11b+; B, B cells, B220+; T, T cells, CD3e+. (B) Flow cytometry plots illustrating the gating strategy for MDSCs in cells from A. gMDSC, granulocytic MDSC. (C) Quantification of MDSC populations in B. (D) Flow cytometric analyses of the expression levels of c-Kit among the indicated cell populations from C in the indicated mice. (E) Absolute numbers of cells in the indicated lineages were quantified in the bone marrow and spleens from the indicated mice in A. (F) Cell size of indicated MDSCs in E was measured by flow cytometric forward scatter (FSC-A) and normalized to cells from the TWT group. (G) Absolute number of erythroid cells in various developmental stages (I–VI) from the bone marrow and spleens of the indicated mice in C. The stages were determined by the cell surface expression levels of CD44. Stage I, proerythroblast; stage II, basophilic erythroblast; stage III, polychromatic erythroblast; stage IV, orthochromatic erythroblast; stage V, reticulocyte; stage VI, mature erythrocyte. Data are presented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001; 2-way ANOVA.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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