Clarifying immunoglobulin gene usage in systemic and localized immunoglobulin light-chain amyloidosis by mass spectrometry

Kourelis, Taxiarchis; Dasari, Surendra; Theis, Jason D.; Ramı́rez-Alvarado, Marina; Kurtin, Paul J.; Gertz, Morie A.; Zeldenrust, Steven R.; Zenka, Roman M.; Doğan, Ahmet; Dispenzieri, Angela

doi:10.1182/blood-2016-10-743997

Cited by 104 publications

(107 citation statements)

References 39 publications

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“…The reasons related to low light chain burden in renal AL amyloidosis are probably multi‐factorial. It is now well described that germline immunoglobulin lambda variable gene ( IGLV ) usage is associated with organ tropism in AL amyloidosis and may also partly explain the amyloidogenicty of light chains (Comenzo et al , ; Kourelis et al , ). There is also some data to suggest that post‐translational modifications that alter the structure of light chains, like glycosylation, also contribute to amyloidogenicity (Omtvedt et al , ; Connors et al , ; Milani et al , ).…”

Section: Discussionmentioning

confidence: 99%

“…The reasons related to low light chain burden in renal AL amyloidosis are probably multi-factorial. It is now well described that germline immunoglobulin lambda variable gene (IGLV) usage is associated with organ tropism in AL amyloidosis and may also partly explain the amyloidogenicty of light chains (Comenzo et al, 2001;Kourelis et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

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Clinical features, laboratory characteristics and outcomes of patients with renal versus cardiac light chain amyloidosis

et al. 2019

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Summary This study evaluated the differences in clinical features of 1077 newly diagnosed AL amyloidosis patients with renal involvement (n = 229, 21%), both cardiac and renal involvement (n = 443, 41%) and cardiac involvement (n = 405, 38%). Significant differences in dFLC (difference in involved and uninvolved light chains) were noted (renal, both, cardiac median: 83, 234 and 349 mg/l, P < 0.001). The proportion of patients with ≥ 10% bone marrow plasma cells (BMPCs) was lowest in renal only patients: 44%, 57%, 64%, respectively, P < 0.001. In a multivariate linear regression model incorporating organ involvement type and BMPCs ≥10%, organ involvement was a significant predictor of dFLC (P < 0.001). Median overall survival (OS) across the three groups was 83 vs. 19 vs. 16 months (P < 0.001) in patients not undergoing transplant and 5‐year OS in patients undergoing transplant was 90% vs. 75% vs. 64% (P = 0.007), respectively. In conclusion, renal involvement alone or renal + cardiac involvement in AL amyloidosis is associated with lower circulating light chain burden, which cannot be fully explained by BMPC burden alone. Increased sensitivity of the kidney to light chains, given significant interactions with the renal tubular system and secretion of modified light chain products may play a role in pathogenesis of renal AL amyloidosis and warrants further investigation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Clinical features, laboratory characteristics and outcomes of patients with renal versus cardiac light chain amyloidosis

et al. 2019

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“…We did not find any correlation between MAGE CT gene expression and a propensity to specific affected organs (organ tropism). Organ tropism has been reported to be partially related to PC clones derived from particular IGLV genes . Our observations in this study suggested that MAGE genes may not be potential factors regulating organ tropism.…”

Section: Discussionmentioning

confidence: 99%

MAGE genes: Prognostic indicators in AL amyloidosis patients

Liu

Wen

et al. 2019

J Cellular Molecular Medi

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A high frequency of MAGE‐CT (cancer testis) antigens are expressed in Multiple Myeloma (MM) patients; however, in other plasma cell dyscrasias, their potential function remains unclear. We measured the expression of MAGE‐CT genes (MAGE‐C1/CT7, MAGE‐A3, MAGE‐C2/CT10) in 105 newly diagnosed amyloid light‐chain (AL) amyloidosis patients between June 2013 and January 2018 at Peking University People's Hospital using real‐time quantitative polymerase chain reaction. In the newly diagnosed AL patients, the positive expression rates of patients with MAGE‐C1/CT7, MAGE‐C2/CT10 and MAGE‐A3 were 83.8% (88/105), 56.71% (38/67) and 22.0% (13/59) respectively. There was no significant correlation between organ propensity and MAGE‐CT gene expression. Changes in the MAGE‐C1/CT7 levels were consistent with a therapeutic effect. The expression levels of MAGE‐C1/CT7, MAGE‐C2/CT10 and MAGE‐A3 provide potentially effective clinical indicators for auxiliary diagnoses and monitoring treatment efficacy in AL amyloidosis patients.

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“…It seems unlikely, however, that such damage could be related to the type of light chain as suggested by others (23), since the majority of cerebral amyloidomas (as systemic AL amyloidosis) is characterized by lambda light chain restriction. Interestingly, a recently published study suggests different light-chain variable region (IGVL) gene usage between systemic and localized AL amyloidosis (6). There is some consensus on the diagnosis and therapy of extracerebral amyloidosis (16), but guidelines for the treatment of cerebral amyloidoma are lacking.…”

Section: Discussionmentioning

confidence: 99%

Cerebral amyloidoma is characterized by B‐cell clonality and a stable clinical course

et al. 2017

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Amyloidomas are rare amyloid-containing lesions, which may also occur in the central nervous system. Etiology, pathogenesis and clinical course are poorly understood. To gain more insight into the biology of cerebral amyloidoma, they aimed to characterize its histopathological, molecular and clinical features in a retrospective series of seven patients. FFPE tissue specimens were examined using immunohistochemistry, chromogenic in situ hybridization (CISH) for light chains kappa and lambda as well as an IgH gene clonality analysis. Follow-up information was gathered by reviewing patient records and imaging results. Median age of the three males and four females was 50 years (range: 35-53 years). All cerebral amyloidomas were located supratentorially and were classified as lambda light chain amyloidosis (AL-λ; n = 6) and kappa light chain amyloidosis (AL-κ; n = 1) on immunohistochemistry and CISH. B-cell clonality was confirmed by IgH gene clonality assay in all cases examined. After a median follow-up of 21 months, all patients were alive and showed stable disease. No progression to systemic disease was observed. In conclusion, their data suggest that cerebral amyloidoma is a local disease characterized by B-cell clonality and associated with a stable clinical course.

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Clarifying immunoglobulin gene usage in systemic and localized immunoglobulin light-chain amyloidosis by mass spectrometry

Abstract: Key Points Mass spectrometry is a high-throughput, low-resource technique that can identify immunoglobulin variable region gene from tissue specimens. IGVL gene usage is restricted and different between systemic and localized AL and only partially explains organ tropism in this disease.

Cited by 104 publications

References 39 publications

Clinical features, laboratory characteristics and outcomes of patients with renal versus cardiac light chain amyloidosis

Clinical features, laboratory characteristics and outcomes of patients with renal versus cardiac light chain amyloidosis

MAGE genes: Prognostic indicators in AL amyloidosis patients

Cerebral amyloidoma is characterized by B‐cell clonality and a stable clinical course

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