Proteomic profiling of amyloid deposits in advanced systemic light-chain (AL) amyloidosis: Insights into clonal light chains, chaperone proteins, and cardiac involvement

作者：Piaorong Zeng, Yangqiu Li, Yikai Zhang, Jing Lai, Qiuyang Dong, Li-Ye Zhong · 发表于：Blood · 年份：2025 · DOI：10.1182/blood-2025-2189 · 研究领域：Amyloidosis: Diagnosis, Treatment, Outcomes、Multiple Myeloma Research and Treatments、Alzheimer's disease research and treatments

Abstract Background: Systemic light-chain (AL) amyloidosis with advanced cardiac involvement is associated with markedly reduced survival. The extent of organ deposition is highly correlated with the sequence specificity of the variable domain (VL) of the clonal immunoglobulin light chain. However, VL sequence alone does not fully account for the severity of organ involvement. To better elucidate the pathogenic mechanism underlying AL amyloid formation, we performed proteomic analysis of Congo red–positive amyloid deposits to characterize the composition of clonal light chains and associated chaperone proteins and to explore their relationship with cardiac involvement. Methods: Laser microdissection followed by LC-MS/MS was performed on Congo red–positive tissues from 76 newly diagnosed AL amyloidosis patients. A total of 425 proteins were quantified. Customized peptide libraries enabled precise typing of light chain VL domains. Unsupervised clustering was applied to proteomic profiles from patients with cardiac involvement. Results: Mass spectrometry revealed that successful VL subtyping relied on the presence of key chaperone proteins—Vitronectin (VTNC), Apolipoprotein A-IV (ApoA4), Apolipoprotein E (ApoE), Serum amyloid P-component (SAMP). When any of these proteins were absent, the subtyping failure rate increased from 4.4% to 62.5% (OR = 36.1, 95% CI 6.3–272; P < 0.001), particularly among patients with lower NT-proBNP and earlier Mayo stage. The IGLV6-57 gene was...