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

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.