Transcriptional Profiling of Plasma Cells in AL Amyloidosis and Multiple Myeloma: A Single-Cell RNA Sequencing Approach

Background

AL amyloidosis, characterized by the deposition of amyloid fibrils derived from monoclonal light chains, often results in multi-organ dysfunction. Timely diagnosis is crucial for effective management. The gold standard for AL amyloidosis diagnosis involves the demonstration of amyloid deposits by biopsy, usually in affected organs. Despite their potential co-occurrence between multiple myeloma (MM) and AL amyloidosis, distinguishing AL amyloidosis within the context of MM poses diagnostic challenges.

Method

By single-cell RNA sequencing (scRNA-seq), we investigated bone marrow aspirates of 8 treatment-naïve AL amyloidosis, 18 treatment-naïve MM. Publicly available scRNA-seq data of BM-MNCs from 23 healthy donors were used as normal control.

Results

Utilizing single-cell RNA sequencing, we identified 37 distinct subtypes of plasma cells, with the majority being MM-specific and showing patient-specific independence. In contrast, control and AL groups exhibited a more convergent pattern, comprising 1-2 plasma cell subsets. We discovered gene expression differences among plasma cells in control, AL, and MM groups. Through comparative analysis of up-regulated and down-regulated genes, we identified 2,342 potential candidates specific to AL amyloidosis, of which 1,598 were up-regulated and 744 were down-regulated. Focusing on tier-1 genes with possible driver mutations and confirming gene nature related to protein metabolism disorders, we selected 54 genes unique to AL amyloidosis compared to MM or healthy controls. To develop a transcriptional biomarker panel for AL amyloidosis, we further refined the selection to 31 genes that facilitated panel construction, including two housekeeping genes and 14 genes with the highest statistical significance for panel development QC. Ultimately, we assembled a transcriptome panel consisting of 47 genes, specific to the diagnosis of AL amyloidosis.

Conclusion

This panel has the potential to aid in the identification of patients with asymptomatic plasma cell dyscrasia who should undergo amyloidosis tissue testing. However, its validation status necessitates further assessment in a validation cohort.

Park:ImpriMed, Inc.: Consultancy, Current holder of stock options in a privately-held company. Kim:AbbVie, AIMS Bioscience, AML-Hub, Astellas, BMS & Celgene, Boryung Pharm Co., Daiichi Sankyo, Janssen, Handok, LG Chem, Novartis, Pfizer, SL VaxiGen, VigenCell, Aston Bioscience, Ingenium, Amgen, Sanofi Genzyme, Takeda, Meiji Pharm Co. and GreenCross Phar: Consultancy; AbbVie, Astellas, BMS, Handok, Novartis, AML-Hub, Jazz Pharmaceuticals and Takeda: Honoraria, Speakers Bureau; BL&H: Research Funding; BMS & Celgene, Novartis, APLC, AbbVie, Astellas, Janssen, Handok, Pfizer, Sanofi Genzyme, AML-Hub, Daiichi Sankyo and APBMT: Membership on an entity's Board of Directors or advisory committees.