(PA-217) Potential Roles of YBX1-MIF Axis in Promoting Bone Marrow Inflammation and Multiple Myeloma Progression

Bone marrow inflammation is considered as a driver of multiple myeloma (MM) progression; however, underlying mechanisms remain to be elucidated.

Methods:   

The bulk RNA-Seq data were downloaded from Multiple Myeloma Research Foundation (MMRF) CoMMpass dataset. Single cell RNA-seq datasets were downloaded from the GeneExpression Omnibus (GEO) database (GSE124310, GSE189460, GSE223060, GSE161801), and ArrayExpress (E-MTAB-9139) covering disease spectrum from MGUS, SMM to NDMM and RRMM as well as healthy condition. Single-cell data was integrated and a total of 1,220,829 cells were captured, downstream analysis was performed majorly using Seurat R package. Each cell cluster was annotated by canonical markers.

Results:   By comparing gene expression profile of myeloma cells and other major cell types including T, NK, B, monocytes, macrophage, neutrophil, DC and erythroid cells, we found that MIF (migration inhibitory factor) showed the strongest expression level in myeloma cells. And its expression gradually increased during disease progression. Cell-cell interactions results indicated that MIF-CD74/CXCR4/CD44 ligand-receptor pairs mediate the most prominent interaction between myeloma cells and myeloid subsets. By exploring the potential factor regulating MIF expression in MM, we found that transcription factor YBX1 showed a positive correlation with MIF, suggesting YBX1 may promote myeloma-derived MIF expression and secretion. YBX1-high MM patients exhibited stronger interaction of MIF-CD74/CXCR4/CD44 between myeloma cells and each myeloid subset. Furthermore, inflammatory pathways (interferon response, inflammatory response, cell adhesion, leukocyte migration) and proinflammatory genes (IL1B, CCL2, CCR2, ISG15, MX1, IL15, IL16, CX3CR1) were significantly enhanced in myeloid subsets from YBX1-high MM patients.

Conclusions:   

MM-derived MIF may be regulated by YBX1 and promote myeloid cell-mediated inflammatory response, thus promote disease progression. Detailed mechanisms warrant further exploration.