<scp>AL</scp> amyloidosis clonal plasma cells are regulated by <scp>microRNAs</scp> and dependent on anti‐apoptotic <scp>BCL2</scp> family members

Fishov, Hila; Muchtar, Eli; Salmon‐Divon, Mali; Dispenzieri, Angela; Zvida, Tal; Schneider, Claudio; Bender, Benjamin; Duek, Adrian; Leiba, Merav; Shpilberg, Ofer; Hershkovitz‐Rokah, Oshrat

doi:10.1002/cam4.5621

Cited by 4 publications

(1 citation statement)

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“…Numerous attempts have been made to decipher the onset and progression of the AL pathological process, from amyloidogenic LC secretion to fibrillar deposit formation and organ tropism. Information on the general steps leading LCs to misfold and aggregate has been obtained from in vitro studies [11][12][13][14][15][16][17][18] . Experiments conducted in cardiomyocytes and cardiac fibroblasts provided advances in the mechanism of LC toxicity, showing that soluble oligomers and amyloidogenic deposits are both key players 14,[19][20][21][22] .…”

Section: Introductionmentioning

confidence: 99%

Modeling immunoglobulin light chain amyloidosis inCaenorhabditis elegans

Romeo,

Barzago,

Corbelli

et al. 2024

Preprint

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Cardiac involvement determines the survival of patients with immunoglobulin light chain (AL) amyloidosis, a rare systemic disease caused by the misfolding and deposition of monoclonal light chains (LCs). The reasons underlining their cardiac tropism remain unknown, and an animal model recapitulating the main pathological features of AL amyloidosis is instrumental. Taking advantage of the similarities between the vertebrate heart andC. elegans’ pharynx, we developed a new transgenic nematode expressing a human amyloidogenic λ LC whose sequence was deduced from an AL-affected patient with cardiac involvement (MNH). Strains expressing a non-amyloidogenic LC (MNM) or the empty vector only (MNV) were generated as controls. At variance with controls, LCs expressed in the body-wall muscle of MNH worms formed native soluble dimeric assemblies, which were secreted and reached different organs, including the pharynx. Noteworthy, MNH worms exerted a pharyngeal impairment resembling the bradycardia occurring in AL-affected patients, accompanied by increased radical oxygen species production and tissue ultrastructural damage. This new animal model can allow the elucidation of the mechanisms underlying the cardiac-specific tropism occurring in AL amyloidosis, providing innovative insights into the pathophysiology.Summary StatementWe generated a newC. elegansanimal model of cardiac AL amyloidosis. This model represents a uniquein vivotool for studying the cardiac-specific damage occurring in the disease.

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Section: Introductionmentioning

confidence: 99%

Modeling immunoglobulin light chain amyloidosis inCaenorhabditis elegans

Romeo,

Barzago,

Corbelli

et al. 2024

Preprint

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AL amyloidosis clonal plasma cells are regulated by microRNAs and dependent on anti‐apoptotic BCL2 family members

et al. 2023

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Three years follow-up of Venetoclax in advanced-stage, relapsed or refractory AL amyloidosis with cardiac involvement and t(11;14) with BCL2 expression

Rieger,

Pabst,

Jeker

et al. 2024

Ann Hematol

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Further line treatment of patients with advanced stage AL amyloidosis with cardiac involvement is challenging. Venetoclax is a promising option, especially in t(11;14) and BCL2 expression.In our multicentre observational study, we report the 3-year follow-up of Venetoclax treatment in 9 patients with advanced, relapsed or refractory AL amyloidosis with t(11;14) and BCL-2 expression in > 50% of plasma cells. At baseline, all patients had been previously treated with daratumumab, all had cardiac involvement with revised Mayo stage III or IV/ European modification of Mayo 2004 IIIA or IIIB (1/9 unclassified due to missing troponin T), 5/9 patients had renal involvement.After a median of 35 months (range 25–49) since the start of Venetoclax, 8/9 patients were still alive (OS 89%). First and best hematological responses were observed after a median of 26 days (11–125) and 106 days (35–659), overall response rate was 100% (7/9 CR, 2/9 VGPR). Where observed, organ response was documented within the first 6 months of therapy, including cardiac (6/9) and renal (3/5) improvements. Venetoclax was discontinued in 6/9 patients after a median of 15 months (11–48) due to toxicity (2/9), disease progression (2/9), fixed treatment duration (1/9), or safety concerns (1/9).In conclusion, Venetoclax induces a rapid and deep hematologic response with consistent improvement in organ function with an acceptable safety profile in patients with pretreated, advanced stage AL amyloidosis with cardiac involvement and BCL2 expression with and potentially without detected t(11:14), which warrants further investigation.

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AL amyloidosis clonal plasma cells are regulated by microRNAs and dependent on anti‐apoptotic BCL2 family members

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 4 publications

References 52 publications

Modeling immunoglobulin light chain amyloidosis inCaenorhabditis elegans

Modeling immunoglobulin light chain amyloidosis inCaenorhabditis elegans

AL amyloidosis clonal plasma cells are regulated by microRNAs and dependent on anti‐apoptotic BCL2 family members

Three years follow-up of Venetoclax in advanced-stage, relapsed or refractory AL amyloidosis with cardiac involvement and t(11;14) with BCL2 expression

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