Functional Subsets of Plasma Cells Associated with Amyloid Production and Venetoclax Sensitivity in Light Chain Amyloidosis

Abstract Light-chain amyloidosis (AL) is characterised by a systematic deposition of amyloidogenic immunoglobulin light chains produced by pathogenic bone marrow plasma cells (BMPCs), the features of which remain elusive. Herein, we conducted a single-cell RNA-seq and image flow cytometry analysis of BMPCs in AL in comparison with those in healthy controls and their precursors: monoclonal gammopathy of undetermined significance (MGUS). We identified seven BMPC subsets with overlapping but distinct functions such as DNA repair, cell proliferation, osteoclast differentiation, chromatin organisation, and immunoglobulin production. The subsets enriched in AL overexpressed amyloid-beta binding protein-encoding genes, such as apolipoprotein E (APOE) and cystatin 3 (CST3), and exhibited plasmablastic morphology. The subsets related to aberrant light-chain production in AL upregulated pathways of neutrophil degranulation and transportation to as well as modifications in the Golgi apparatus, especially that of N-linked protein glycosylation. The predominant subset was most susceptible to glucocorticoid and proteasome inhibitors and highly expressed venetoclax sensitivity-associated genes in t(11;14) AL. We further validated a patient subgroup featuring a larger proportion of the predominant subset and a higher expression of cyclin D1 (CCND1) and venetoclax sensitivity-associated genes. Our findings provide insights into the mechanisms underlying the functional heterogeneity of BMPCs in AL.