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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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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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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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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DOI: https://doi.org/10.1038/s41375-022-01748-1
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