Intratumor Heterogeneity of MIF Expression Correlates With Extramedullary Involvement of Multiple Myeloma

作者：Juan Xu, Nanhui Yu, Pan Zhao, Fangfang Wang, Jingcao Huang, Yushan Cui, Hong Ding, Yan Yang, Yuhan Gao, Ling Pan, Hong Chang, Yu Wu, Bing Xiang, Yuping Gong, Shuai Xiao, Li Hou, Liping Xie, Ting Niu, Ting Liu, Li Zhang, Weiping Liu, Wenyan Zhang, Ying Qu, Wei Lin, Yimin Zhu, Sha Zhao, Yuhuan Zheng · 发表于：Frontiers in Oncology · 年份：2021 · DOI：10.3389/fonc.2021.694331 · 被引用次数：21 · 研究领域：Macrophage Migration Inhibitory Factor、Galectins and Cancer Biology、Nuclear Receptors and Signaling

Macrophage migration inhibitory factor (MIF) has been shown to promote disease progression in many malignancies, including multiple myeloma (MM). We previously reported that MIF regulates MM bone marrow homing and knockdown of MIF favors the extramedullary myeloma formation in mice. Here, based on MIF immunostaining of myeloma cells in paired intramedullary and extramedullary biopsies from 17 patients, we found lower MIF intensity in extramedullary MM (EMM) versus intramedullary MM (IMM). Flow cytometry and histology analysis in xenograft models showed a portion of inoculated human MM cells lost their MIF expression (MIF Low ) in vivo . Of note, IMM had dominantly MIF High cells, while EMM showed a significantly increased ratio of MIF Low cells. Furthermore, we harvested the extramedullary human MM cells from a mouse and generated single-cell transcriptomic data. The developmental trajectories of MM cells from the MIF High to MIF Low state were indicated. The MIF High cells featured higher proliferation. The MIF Low ones were more quiescent and harbored abundant ribosomal protein genes. Our findings identified in vivo differential regulation of MIF expression in MM and suggested a potential pathogenic role of MIF in the extramedullary spread of disease.