Cellular diversity and genetic alterations in light chain amyloidosis and amyloidosis with co-occurring multiple myeloma

Immunoglobulin light-chain amyloidosis (AL) has been reported to be associated with multiple myeloma (MM) in approximately 10-15% of cases, with the two conditions often coexisting. Understanding the interaction between these diseases is vital for improving patient outcome and developing targeted treatments. Our study investigates cellular heterogeneity in immunoglobulin light-chain amyloidosis (AL) and coexisting multiple myeloma (MM) or monoclonal gammopathy of undetermined significance (MGUS) (AL_MM) using single-cell RNA sequencing (scRNA-seq). A total of 21 bone marrow samples from 20 patients were analyzed, including 9 with AL_MM. We observed exclusive association of the 1q gain chromosomal aberration with the AL_MM group (p<0.01). The scRNA-seq data revealed 27 distinct cell clusters representing 14 unique cell types, with 6 clusters identified as plasma cell (PC) subpopulations. These subpopulations exhibited considerable inter- and intra-individual heterogeneity. Comparative analysis between the AL and AL_MM groups showed higher proportions of GMP, HSC, cDC2, and T cells in the AL group (p<0.05), suggesting a distinct tumor microenvironment. Differential gene expression analysis between the two groups identified 152 up-regulated and 134 down-regulated genes in AL_MM samples, with 28 of the up-regulated genes and 1 downregulated gene located on chromosome 1q. Furthermore, the application of inferCNV to the scRNA-seq data revealed amplifications in chromosome 4, 7, 11, 20, and 22 of AL samples. Our findings enhance the understanding of the molecular mechanisms underlying AL and its progression in patients with coexisting MM or MGUS. The study provides valuable insights into disease progression and cellular variability, supporting improved patient stratification and the development of targeted therapies for these complex hematological conditions. KEY POINTSO_LI1q gain is mainly restricted to amyloidosis patients with co-occurring sMM, MM, or MGUS. C_LIO_LIMultiple genes located on chromosome 1 are upregulated in plasma cells of patients with co-occurring AL and MM, potentially contributing to disease progression. C_LI