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ACUTE MYELOID LEUKEMIA

Loss of bisecting GlcNAcylation on MCAM of bone marrow stoma determined pro-tumoral niche in MDS/AML

Leukemia volume 37, pages 113–121 (2023)Cite this article

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Abstract

Bone marrow (BM) stroma plays key roles in supporting hematopoietic stem cell (HSC) growth. Glycosylation contributes to the interactions between HSC and surrounding microenvironment. We observed that bisecting N-acetylglucosamine (GlcNAc) structures, in BM stromal cells were significantly lower for MDS/AML patients than for healthy subjects. Malignant clonal cells delivered exosomal miR-188-5p to recipient stromal cells, where it suppressed bisecting GlcNAc by targeting MGAT3 gene. Proteomic analysis revealed reduced GlcNAc structures and enhanced expression of MCAM, a marker of BM niche. We characterized MCAM as a bisecting GlcNAc-bearing target protein, and identified Asn 56 as bisecting GlcNAc modification site on MCAM. MCAM on stromal cell surface with reduced bisecting GlcNAc bound strongly to CD13 on myeloid cells, activated responding ERK signaling, and thereby promoted myeloid cell growth. Our findings, taken together, suggest a novel mechanism whereby MDS/AML clonal cells generate a self-permissive niche by modifying glycosylation level of stromal cells.

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Fig. 1: Expression of bisecting GlcNAc in BM stromal cells.
Fig. 2: Bisecting GlcNAc in NBM stroma affects myeloid cell proliferation.
Fig. 3: Exosomal miR188-5p inhibits bisecting GlcNAc by targeting MGAT3.
Fig. 4: Identification and function of bisecting GlcNAcylated MCAM in BM stroma.
Fig. 5: Effect of bisecting GlcNAc modification of MCAM on myeloid cell proliferation.
Fig. 6: Interaction of KG1a membrane proteins with stromal cell MCAM.

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The data supporting the conclusions of this article have been given in this article and its additional files.

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Funding

This study was supported by the National Science Foundation of China (No. 32071274, 82100148, 31971211), Science Foundation for Distinguished Young Scholars of Shaanxi Province (2021JC-39), the Natural Science Foundation of Shaanxi Province (2021SF-294), and the Youth Innovation Team of Shaanxi Universities.

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  1. These authors contributed equally: Jingjing Feng, Yi Wang.

Authors and Affiliations

  1. Institute of Hematology, Provincial Key Laboratory of Biotechnology, School of Medicine, Northwest University, Xi’an, China

    Jingjing Feng, Bingxin Li, Xinwen Yu, Lei Lei, Jinpeng Wu, Xin Zhang, Yue Zhou, Junjie Gou, Hongjiao Li, Zengqi Tan & Xiang Li

  2. Department of Hematology, Provincial People’s Hospital, Xi’an, China

    Yi Wang

  3. BGI-Shenzhen, Shenzhen, China

    Qiushi Chen

  4. Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi’an, China

    Hongjiao Li & Feng Guan

  5. Department of Breast Surgery, the First Affiliated Hospital, Zhejiang University, Hangzhou, China

    Zhijun Dai

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  1. Jingjing Feng
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Contributions

XL and FG conceived the study. JF, YW, BL, XY, LL, JW, XZ, QC, YZ, JG, HL, ZT and ZD performed the experiments and data analysis. FG and XL supervised research and wrote the paper. All authors read and approved the final paper.

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Correspondence to Xiang Li or Feng Guan.

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Feng, J., Wang, Y., Li, B. et al. Loss of bisecting GlcNAcylation on MCAM of bone marrow stoma determined pro-tumoral niche in MDS/AML. Leukemia 37, 113–121 (2023). https://doi.org/10.1038/s41375-022-01748-1

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