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.
Study Type
OBSERVATIONAL
Enrollment
100
Fondazione IRCCS Policlinico San Matteo di Pavia
Pavia, PV, Italy
RECRUITINGDataset of full-length LC variable region sequences
Generation of a clinically annotated dataset of full-length immunoglobulin light chain (LC) variable region sequences derived from the largest reported series of patients with AL and MGUS, including clonal characterization and clinical annotation.
Time frame: two years
Clinical correlates of LC N-glycosylation
Identification of clinical features associated with LC N-glycosylation; evaluation of the impact of LC N-glycosylation on current assays for M-protein identification/quantification and amyloid typing; exploration of potential corrective measures if assay interference is demonstrated.
Time frame: two years
Refinement of sequence-based prediction of LC amyloidogenicity
Validation of existing algorithms/scoring systems for predicting LC amyloidogenicity using newly generated sequences; development of an improved prediction algorithm incorporating sequence and structural/spatial features associated with LC N-glycosylation.
Time frame: two years
Biologic and pharmacologic correlates of LC N-glycosylation
Comparative transcriptional profiling of plasma cell clones expressing unglycosylated versus N-glycosylated LCs; assessment of differential sensitivity to anti-plasma cell drugs and small-molecule inhibitors targeting N-glycosylation pathways.
Time frame: two years
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