Tumor cells in light-chain amyloidosis and myeloma show distinct transcriptional rewiring of normal plasma cell development

Abstract

Although light-chain amyloidosis (AL) and multiple myeloma (MM) are characterized by tumor plasma cell (PC) expansion in bone marrow (BM), their clinical presentation differs. Previous attempts to identify unique pathogenic mechanisms behind such differences were unsuccessful, but there are no studies investigating the differentiation stage of tumor PCs in patients with AL and MM. We sought to define a transcriptional atlas of normal PC development (n=11) in secondary lymphoid organs (SLO), peripheral blood (PB) and BM for comparison with the transcriptional programs (TPs) of tumor PCs in AL (n=37), MM (n=46) and MGUS (n=6). Based on bulk and single-cell RNAseq, we observed thirteen TPs during transition of normal PCs throughout SLO, PB and BM; that CD39 outperforms CD19 to discriminate new-born from long-lived BM-PCs; that tumor PCs expressed the most advantageous TPs of normal PC differentiation; that AL shares greater similarity to SLO-PCs whereas MM is transcriptionally closer to PB-PCs and new-born BM-PCs; that AL and MM patients enriched in immature TPs had inferior survival; and that TPs related with protein N-linked glycosylation are upregulated in AL. Collectively, we provide a novel resource to understand normal PC development and the transcriptional reorganization of AL and other monoclonal gammopathies.

Single-Cell Transcriptomics Reveals the Expression of Aging- and Senescence-Associated Genes in Distinct Cancer Cell Populations

“…Transcriptome-wide analyses on a single cell level of human CML, CRC, HCC, LC, and PDAC were based on previously published scRNA-seq datasets [49][50][51][52][53]. Within the CML dataset, plasma cells from multiple myeloma (MM) patients were used.…”

“…For the comparison of all ASIGs, three healthy bone marrow plasma cell samples (GSM5332301, GSM5332302, and GSM5332303) were included. The annotation was provided by the authors of the original study, and only plasma cells were provided ("orig.ident") [49]. Subsequently, healthy plasma cells were used as controls for comparison purposes, and "MM" samples as malignant samples.…”

“…In contrast, scRNA-seq allows the separation and analysis of distinct cell populations [62]. Therefore, we analyzed publicly available scRNA-seq datasets [49][50][51][52][53] and focused on cell types that were described as putative origins of malignant transformation (MM: plasma cells [63]; CRC: epithelial cells [64]; HCC: hepatocytes [65]; LC: epithelial cells [66]; PDAC: ductal cells [67]). We first compared control and malignant samples (Figure S4B, not provided for CML GSE175385), and except for the PDAC dataset (PR-JCA001063), we found no significant age differences, which is why we decided to compare malignant and control cells exclusively from the same sample in the PDAC dataset (ductal cell type 1 cells = control and ductal cell type 2 = malignant).…”

T cell landscape and dynamics in immunoglobulin light chain amyloidosis before and after daratumumab‐based therapy

“…1 The pathogenesis of AL remains less well understood. [2][3][4] Less than 25% of AL patients with the current mainstay chemotherapy such as a combination of bortezomib, cyclophosphamide and dexamethasone (BCD or CyBorD), and hematopoietic stem cell transplantation achieves a complete and long-lasting haematological remission and survive for more than 10 years. 5,6 In particular, AL patients with the most common chromosomal abnormality (t (11;14)) had a poor haematologic response and shorter survival when treated with BCD.…”

“…17,18 High haematological and organ response rates were reported by various groups, indicating that Dara-based regimens induce a strong antitumour effect in AL even though MM-and AL-derived PCs showed differences in their transcriptomic features and chromosomal abnormalities. 4,[18][19][20][21][22][23] The treatment with Dara in MM patients has been shown to modulate anti-tumour T cell response by reducing CD38 + regulatory T cells (Tregs) and expanding CD3 + T cells (CD8 + T cells in particular) with a skewed T cell repertoire. [24][25][26][27][28] Whether and how Dara-based therapy affects T cells in AL amyloidosis is not clear.…”