Investigating the Pathogenic Role of N-glycosylation in AL Amyloidosis: Molecular Bases, Diagnosis, and Treatment

Summary

Immunoglobulin light chain (AL) amyloidosis is caused by a typically small, minimally proliferating bone marrow plasma cell clone secreting a patient-unique, unstable, aggregation-prone, toxic light chain (LC). The amyloidogenicity of LCs is encrypted in their sequence, yet molecular determinants of LC pathogenicity remain obscure. N-glycosylation has been long suspected to be a determinant of LC amyloidogenicity based on anecdotal reports of individual AL patients with a clonal LC displaying this post-translational modification. It is hypothesized that N-glycosylation fundamentally contributes to determining the amyloidogenicity of immunoglobulin LCs in a subset of patients with AL and might influence its clinical phenotype. It is further proposed that the synthesis and secretion of unstable LCs that also have to be N-glycosylated might reverberate on the biology of the plasma cell clone, possibly modulating the sensitivity toward different drugs and might represent itself a therapeutic target. The objective of our study is now to elucidate the molecular role of LC N-glycosylation in AL amyloidosis, exploit it for risk assessment, and define its potential impact on the biology of the underlying plasma cell clone and its drug sensitivity.

Eligibility

Inclusion Criteria:

* Diagnosis of monoclonal gammopathy (e.g. AL amyloidosis, MGUS, MM, others)
* Planned peripheral blood sampling +/- bone marrow aspiration
* Age \> 18 years
* Willingness to allow use of clinical data and diagnostic leftovers of clinical specimens for research purposes through signing a written informed consent.

Exclusion Criteria:

* Lack of monoclonal gammopathy
* Patients fulfilling the criteria for complete hematologic response after anti-clonal therapy
* Age \<18 years
* Failure to show willingness to allow use of clinical data and diagnostic leftovers of clinical specimens for research purposes.

Conditions5

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