Sequence diversity of kappa light chains from patients with AL amyloidosis and multiple myeloma

Abstract

Background

AL amyloidosis (AL) results from the misfolding of immunoglobulin light chains (IG LCs). Aim of this study was to comprehensively analyse kappa LC sequences from AL patients in comparison with multiple myeloma (MM).

Objective

We analysed IGKV/IGKJ usage and associated organ tropism and IGKV1/D-33 in terms of mutational analysis and theoretical biochemical properties.

Material and Methods

cDNA and bulk RNA sequencing of the LCs of AL and MM patients.

Results

We studied 41 AL and 83 MM patients showing that IGKV1 was most expressed among kappa AL and MM, with higher frequency in AL (80% vs. 53%, p = .002). IGKV3 was underrepresented in AL (10% vs. 30%, p = .014). IGKJ2 was more commonly used in AL than in MM (39% vs. 29%). Patients with IGKV1/D-33 were associated with heart involvement (75%, p = .024). IGKV1/D-33-segments of AL had a higher mutation count (AL = 12.0 vs. MM = 10.0). FR3 and CDR3 were most frequently mutated in both, with a median mutation count in FR3 being the highest (AL = 4.0; MM = 3.5) and one mutation hotspot (FR3 (83I)) for IGKV1/D-33/IGKJ2 was associated with cardiac involvement.

Conclusion

This study confirmed that germline usage has an influence on AL amyloidosis risk and organ involvement.

Keywords:

• AL amyloidosis
• immunoglobulin light chain
• Ig-kappa light chain
• LC sequence
• multiple myeloma

Acknowledgement

We would like to thank the patients for their support to participate in our study and the clinical Myeloma-Registry and the GMMG Central Lab and Biobank Multiple Myeloma; University Hospital Heidelberg & GMMG e.V.

Disclosure statement

EKM Consulting or Advisory Role, Honoraria, Research Funding, and Travel Accommodations and Expenses—Bristol Myers Squibb/Celgene, GlaxoSmithKline, Janssen-Cilag, Sanofi, Stemline and Takeda. The other authors declare no conflict of interests.

Data availability statement

The data that support the findings of this study are available from the corresponding author, SS and SoS, upon reasonable request. IGKV1/D-33 AL and MM sequence data were stored in the European Nucleotide Archive (accession: PRJEB65847).

Additional information

Funding

This work was funded by the deutsche Forschungsgemeinschaft (Research Unit FOR2969, projects UH: HE 8472/1-1, SOS: SCHO 1364/2-1, SH: HU 2400/1-1) and supported by the Dietmar Hopp Stiftung.