Single-cell and clonal analysis of AL amyloidosis plasma cells and their bone marrow microenvironment.

Abstract

Abstract: AL amyloidosis is a disorder characterized by expansion of clonal plasma cells in the bone marrow and distant end organ damage mediated by misfolded immunoglobulin free light chains. There are currently limited data regarding the functional characteristics of AL amyloidosis plasma cells and their surrounding bone marrow microenvironment. We performed 5' single-cell RNA sequencing on newly diagnosed, treatment-naïve patients with AL amyloidosis and healthy subjects. We identified generalized suppression of normal bone marrow hematopoiesis with distinct expansion of monocytes and subsets of CD4+ T cells in patients with AL amyloidosis. We detected significant transcriptional changes broadly occurring among immune cells with increased tumor necrosis factor-α signaling and interferon response accompanied by increased inflammatory response in bone marrow plasma, as measured via quantitative proteomics with specific elevation of costimulatory molecule soluble CD276 (sB7-H3). A transcriptionally distinct population of nonmalignant plasma cells was disproportionately expanded in patients with AL amyloidosis and characterized by increased expression of CRIP1. Finally, clonal AL amyloidosis plasma cells were identified based on their unique variable-diversity-joining. rearrangement and showed increased expression of genes involved in proteostasis when compared with autologous, polyclonal plasma cells. Interpatient transcriptional heterogeneity was evident, with transcriptional states reflective of common genomic translocations easily identifiable. This study defines the transcriptional characteristics of AL amyloidosis plasma cells and their surrounding bone marrow microenvironment with identification of altered genes previously involved in the pathogenesis of other protein deposition disorders. Our data provide the rationale for functional validations of these genes in future studies.