Aberrant NSUN2-mediated m5C modification of exosomal LncRNA MALAT1 induced RANKL-mediated bone destruction in multiple myeloma.

The impact of exosome-mediated crosstalk between multiple myeloma (MM) cells and osteoclasts (OCs) on bone lesions remains to be investigated. Here, we identified NSUN2 and YBX1-mediated m5C modifications upregulated LncRNA MALAT1 expression in MM cells, which could be transported to OCs via exosomes and promote bone lesions. Methodologically, RNA-seq was carried out to detect the cargoes of exosomes. TRAP staining and WB were used to evaluate osteoclastogenesis in vitro. Micro-CT and bone histomorphometric analyses were performed to identify bone destruction in vivo. RNA pull-down, RIP, MeRIP, and luciferase reporter assays were used to test the interactions between molecules. The clinical features of MALAT1, NSUN2 and YBX1 were verified through public datasets and clinicopathological data analyses. Mechanistically, MALAT1 was the highest expressed lncRNA in U266 exosomes and could be transported to RAW264.7 cells. MALAT1 could enhance the differentiation of RAW264.7 cells into OCs by stimulating RANKL expression and its downstream AKT and MAPKs signaling pathways via a ceRNA mechanism. Additionally, MALAT1 could be modified by NSUN2, an m5C methyltransferase, which in turn stabilized MALAT1 through the "reader" YBX1. Clinical studies indicated a notable positive correlation between MALAT1, NSUN2, YBX1 levels and bone destruction features, as well as with RANKL expression.