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An updated AL-Base reveals ranked enrichment of immunoglobulin light chain variable genes in AL amyloidosis.
Morgan, Gareth; Nau, Allison N; Wong, Sherry; Spencer, Brian H; Shen, Yun; Hua, Axin; Bullard, Matthew J; Sanchorawala, Vaishali; Prokaeva, Tatiana.
Affiliation
  • Morgan G; Boston University Amyloidosis Center, Boston University Chobanian & Avedisian School of Medicine, Boston University Medical Campus, 72 E. Concord St, Boston, MA 02118, USA.
  • Nau AN; Section of Hematology and Medical Oncology, Boston University Chobanian & Avedisian School of Medicine, Boston University Medical Campus, 72 E. Concord St, Boston, MA 02118, USA.
  • Wong S; Boston University Amyloidosis Center, Boston University Chobanian & Avedisian School of Medicine, Boston University Medical Campus, 72 E. Concord St, Boston, MA 02118, USA.
  • Spencer BH; Boston University Amyloidosis Center, Boston University Chobanian & Avedisian School of Medicine, Boston University Medical Campus, 72 E. Concord St, Boston, MA 02118, USA.
  • Shen Y; Boston University Amyloidosis Center, Boston University Chobanian & Avedisian School of Medicine, Boston University Medical Campus, 72 E. Concord St, Boston, MA 02118, USA.
  • Hua A; Boston University Research Computing Services, Boston University Medical Campus, 72 E. Concord St, Boston, MA 02118, USA.
  • Bullard MJ; Biostatistics and Epidemiology Data Analytics Center, Boston University School of Public Health, Boston University Medical Campus, 72 E. Concord St, Boston, MA 02118, USA.
  • Sanchorawala V; Biostatistics and Epidemiology Data Analytics Center, Boston University School of Public Health, Boston University Medical Campus, 72 E. Concord St, Boston, MA 02118, USA.
  • Prokaeva T; Boston University Amyloidosis Center, Boston University Chobanian & Avedisian School of Medicine, Boston University Medical Campus, 72 E. Concord St, Boston, MA 02118, USA.
bioRxiv ; 2024 Sep 15.
Article in En | MEDLINE | ID: mdl-39314448
ABSTRACT

Background:

Each monoclonal antibody light chain associated with AL amyloidosis has a unique sequence. Defining how these sequences lead to amyloid deposition could facilitate faster diagnosis and lead to new treatments.

Methods:

Light chain sequences are collected in the Boston University AL-Base repository. Monoclonal sequences from AL amyloidosis, multiple myeloma and the healthy polyclonal immune repertoire were compared to identify differences in precursor gene use, mutation frequency and physicochemical properties.

Results:

AL-Base now contains 2,193 monoclonal light chain sequences from plasma cell dyscrasias. Sixteen germline precursor genes were enriched in AL amyloidosis, relative to multiple myeloma and the polyclonal repertoire. Two genes, IGKV1-16 and IGLV1-36, were infrequently observed but highly enriched in AL amyloidosis. The number of mutations varied widely between light chains. AL-associated κ light chains harbored significantly more mutations compared to multiple myeloma and polyclonal sequences, whereas AL-associated λ light chains had fewer mutations. Machine learning tools designed to predict amyloid propensity were less accurate for new sequences than their original training data.

Conclusions:

Rarely-observed light chain variable genes may carry a high risk of AL amyloidosis. New approaches are needed to define sequence-associated risk factors for AL amyloidosis. AL-Base is a foundational resource for such studies.
Key words

Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: BioRxiv Year: 2024 Document type: Article Affiliation country: Country of publication:

Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: BioRxiv Year: 2024 Document type: Article Affiliation country: Country of publication: