Single-cell transcriptomics reveals pathogenic interactions between clonal plasma cells and monocytes in POEMS syndrome

Abstract Introduction: POEMS syndrome is a rare plasma cell disorder, primarily characterized by polyneuropathy, organomegaly, endocrinopathy, M-protein abnormalities, and skin changes. It has a low incidence but high mortality and misdiagnosis rates due to complex clinical manifestations. Currently, the understanding of its pathogenesis is limited to the production of clonal plasma cells and elevated VEGF levels. However, the precise molecular mechanisms driving disease progression, particularly the transcriptional dynamics within clonal plasma cells and their interplay with the surrounding immune microenvironment, remain poorly defined. This knowledge gap hinders the development of targeted therapies and accurate diagnostic strategies Aim This study aims to further explore the transcriptional profile characteristics of plasma cells and the immune microenvironment in patients with POEMS syndrome. Methods We collected bone marrow specimens from 6 newly diagnosed POEMS syndrome patients, 5 newly diagnosed Multiple Myeloma (NDMM) patients, and 1 post-treatment POEMS syndrome patient. These specimens were subjected to 10x Genomics 5' single-cell sequencing coupled with B cell repertoire (BCR) sequencing. Additionally, two normal bone marrow samples retrieved from the Gene Expression Omnibus (GEO) database were incorporated for integrative analysis. The entire analytical workflow was performed using R software. Results After quality control, 102,307 cells were included in downstream analyses. Using the Seurat pipeline, we identified cell types including plasma cells, B cells, NK/T cells, monocytes, GMP (granulocyte-monocyte progenitors), cDC cells (conventional dendritic cells), pDC cells (plasmacytoid dendritic cells), HSC (hematopoietic stem cells), and Erythroid cells. First, we conducted subclustering analysis on plasma cells and further characterized the clonal status of individual plasma cells based on their BCR sequences, classifying plasma cells into clonal plasma cells and non-clonal plasma cells. Differential gene and pathway enrichment analyses showed that compared with normal plasma cells (NPC), non-clonal plasma cells in POEMS syndrome (POEMS non-clone), and clonal plasma cells in NDMM (MM clone), clonal plasma cells in POEMS syndrome (POEMS clone) exhibited upregulation of genes related to oxidative phosphorylation and epithelial-mesenchymal transition. POEMS non-clone showed upregulation of interferon responses. After treatment, genes related to oxidative phosphorylation and epithelial-mesenchymal transition in POEMS clone were downregulated, and the interferon response in POEMS non-clone was also downregulated. We also further observed that POEMS-related inflammatory factors such as VEGFA, IL1B, TNF-α, and IL6 are mainly derived from monocytes in the immune microenvironment. Through differential analysis and functional enrichment, we found that monocytes in POEMS syndrome highly upregulated genes related to interferon responses and the TNFα-mediated NFKB pathway, while their adhesion, phagocytosis, and chemotaxis functions were weakened. After treatment, interferon-related genes and TNFα-mediated NFKB-related genes in monocytes of POEMS syndrome were downregulated. Using the CellChat method to analyze the interactions between plasma cells and immune microenvironment cells, we found that the ANXA1-FPR1 axis uniquely acts on monocytes through POEMS clone cells, which may be involved in the occurrence and development of POEMS syndrome. Conclusion Through single-cell sequencing technology, we further identified transcriptional changes in plasma cells and monocytes in patients with POEMS syndrome and found that the ANXA1-FPR1 axis may be involved in the pathogenesis of POEMS syndrome.