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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 8

Tocilizumab reduces cell proliferation and colony formation in MDS patient cells.

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Tocilizumab reduces cell proliferation and colony formation in MDS patie...
(A) Cultured MDSL cells were treated with tocilizumab or IgG for 1 hour at indicated concentrations. Cells were then challenged with human recombinant IL-6 (10 ng/mL) for 15 minutes followed by Western blot assay of p-STAT3. Actin was used as a loading control. See complete unedited blots in the supplemental material. (B) 1 × 104 MDSL cells per well were seeded in a 96-well plate on day 0 in MDSL culture medium with 50 μg/mL tocilizumab or 50 μg/mL human IgG control. Relative cell number was assessed with CCK-8 reagent at indicated time points. (C) 1 × 106 MDSL cells were transplanted into sublethally irradiated NSG recipient mice. Ten days after transplantation, mice were subjected to weekly tocilizumab (TCZ) or human IgG (8 mg/kg) by i.p. administration. Engraftment was evaluated 60 days after transplantation via flow cytometry assays of hCD45+ mononuclear cells in the peripheral blood. n = 5 in each group. (D) Quantification of the percentage of hCD45+ cells in C. (E and F) Colony-forming unit (CFU) assays in normal (E) and high-risk MDS patient (F) bone marrow–derived CD34+ cells. 1 × 103 normal (E) or 2 × 103 patient CD34+ cells (F) were seeded in MethoCult medium supplemented with human IgG or tocilizumab (50 μg/mL) on day 0. The number of colonies was assessed on day 14. Triplicate assay colonies were independently identified by 2 individuals. Data are presented as mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001; 2-tailed Student’s t test. E, G, M, GM, and GEMM represent BFU/CFU-E, CFU-G, CFU-M, CFU-GM, and CFU-GEMM, respectively, in both E and F.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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