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

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

doi:10.1172/JCI152673

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

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 YangPeng Ji^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

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.

Original language	English (US)
Article number	e152673
Journal	Journal of Clinical Investigation
Volume	132
Issue number	17
DOIs	https://doi.org/10.1172/JCI152673
State	Published - Sep 1 2022

Funding

We thank the Comprehensive Metabolic Core, NUSeq Core, and Mouse Histology and Phenotyping Laboratory of Northwestern University for the multiplex ELISA assay, single-cell RNA sequencing analysis, and mouse immunohistochemical stain, respectively. We thank Daniel Starczynowski and Gang Huang for providing the MDSL cell line. This work was supported by Department of Defense grant CA140119 (to PJ), National Institute of Diabetes and Digestive and Kidney Diseases grant R01-DK124220 (to PJ), National Heart, Lung, and Blood Institute grants R01-HL148012 (to PJ) and R01-HL150729 (to PJ), and a Translational Bridge grant from the Robert H. Lurie Comprehen- sive Cancer Center of Northwestern University (to YM, KR, and PJ). PJ is a scholar of the Leukemia and Lymphoma Society and the Harrington Discovery Institute. This work was also partially supported by grants from the Global Research Award from the American Society of Hematology (to YM), the Provincial Natural Science Foundation of Hunan (2021JJ30163 and 2022JJ20021 to YM), the Changsha Municipal Natural Science Foundation (kq2007053 to YM), and the High-Level Talent Research Startup Fund of Hunan University (531119200159 to YM). We thank the Comprehensive Metabolic Core, NUSeq Core, and Mouse Histology and Phenotyping Laboratory of Northwestern University for the multiplex ELISA assay, single-cell RNA sequencing analysis, and mouse immunohistochemical stain, respectively. We thank Daniel Starczynowski and Gang Huang for providing the MDSL cell line. This work was supported by Department of Defense grant CA140119 (to PJ), National Institute of Diabetes and Digestive and Kidney Diseases grant R01-DK124220 (to PJ), National Heart, Lung, and Blood Institute grants R01-HL148012 (to PJ) and R01-HL150729 (to PJ), and a Translational Bridge grant from the Robert H. Lurie Comprehensive Cancer Center of Northwestern University (to YM, KR, and PJ). PJ is a scholar of the Leukemia and Lymphoma Society and the Harrington Discovery Institute. This work was also partially supported by grants from the Global Research Award from the American Society of Hematology (to YM), the Provincial Natural Science Foundation of Hunan (2021JJ30163 and 2022JJ20021 to YM), the Changsha Municipal Natural Science Foundation (kq2007053 to YM), and the High-Level Talent Research Startup Fund of Hunan University (531119200159 to YM).

ASJC Scopus subject areas

General Medicine

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10.1172/JCI152673

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Mei, Y., Ren, K., Liu, Y., Ma, A., Xia, Z., Han, X., Li, E., Tariq, H., Bao, H., Xie, X., Zou, C., Zhang, D., Li, Z., Dong, L., Verma, A., Lu, X., Abaza, Y., Altman, J. K., Sukhanova, M., ... Ji, P. (2022). Bone marrow–confined IL-6 signaling mediates the progression of myelodysplastic syndromes to acute myeloid leukemia. Journal of Clinical Investigation, 132(17), Article e152673. https://doi.org/10.1172/JCI152673

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

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.",

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

note = "Publisher Copyright: {\textcopyright} 2022, Mei et al.",

year = "2022",

month = sep,

day = "1",

doi = "10.1172/JCI152673",

language = "English (US)",

volume = "132",

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Mei, Y, Ren, K, Liu, Y, Ma, A, Xia, Z, Han, X, Li, E, Tariq, H, Bao, H, Xie, X, Zou, C, Zhang, D, Li, Z, Dong, L, Verma, A, Lu, X , Abaza, Y , Altman, JK , Sukhanova, M, Yang, J & Ji, P 2022, 'Bone marrow–confined IL-6 signaling mediates the progression of myelodysplastic syndromes to acute myeloid leukemia', Journal of Clinical Investigation, vol. 132, no. 17, e152673. https://doi.org/10.1172/JCI152673

TY - JOUR

T1 - Bone marrow–confined IL-6 signaling mediates the progression of myelodysplastic syndromes to acute myeloid leukemia

AU - Mei, Yang

AU - Ren, Kehan

AU - Liu, Yijie

AU - Ma, Annabel

AU - Xia, Zongjun

AU - Han, Xu

AU - Li, Ermin

AU - Tariq, Hamza

AU - Bao, Haiyan

AU - Xie, Xinshu

AU - Zou, Cheng

AU - Zhang, Dingxiao

AU - Li, Zhaofeng

AU - Dong, Lili

AU - Verma, Amit

AU - Lu, Xinyan

AU - Abaza, Yasmin

AU - Altman, Jessica K.

AU - Sukhanova, Madina

AU - Yang, Jing

AU - Ji, Peng

PY - 2022/9/1

Y1 - 2022/9/1

N2 - 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.

AB - 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.

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

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