Feng Jingjing, Wang Yi, Li Bingxin, Yu Xinwen, Lei Lei, Wu Jinpeng, Zhang Xin, Chen Qiushi, Zhou Yue, Gou Junjie, Li Hongjiao, Tan Zengqi, Dai Zhijun, Li Xiang, Guan Feng
Institute of Hematology, Provincial Key Laboratory of Biotechnology, School of Medicine, Northwest University, Xi'an, China.
Department of Hematology, Provincial People's Hospital, Xi'an, China.
Leukemia. 2023 Jan;37(1):113-121. doi: 10.1038/s41375-022-01748-1. Epub 2022 Nov 5.
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.
骨髓（BM）基质在支持造血干细胞（HSC）生长中起关键作用。糖基化有助于HSC与周围微环境之间的相互作用。我们观察到，骨髓基质细胞中的平分N-乙酰葡糖胺（GlcNAc）结构在骨髓增生异常综合征/急性髓系白血病（MDS/AML）患者中显著低于健康受试者。恶性克隆细胞将外泌体miR-188-5p传递给受体基质细胞，在那里它通过靶向MGAT3基因抑制平分GlcNAc。蛋白质组学分析显示GlcNAc结构减少，骨髓龛标志物MCAM的表达增强。我们将MCAM鉴定为一种携带平分GlcNAc的靶蛋白，并确定Asn 56为MCAM上的平分GlcNAc修饰位点。基质细胞表面平分GlcNAc减少的MCAM与髓系细胞上的CD13强烈结合，激活反应性ERK信号，从而促进髓系细胞生长。综上所述，我们的研究结果提示了一种新机制，即MDS/AML克隆细胞通过改变基质细胞的糖基化水平来产生自我允许的龛。
