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Kinetic stability and sequence/structure studies of urine-derived Bence-Jones proteins from multiple myeloma and light chain amyloidosis patients.

ABSTRACT: It is now accepted that the ability of a protein to form amyloid fibrils could be associated both kinetic and thermodynamic protein folding parameters. A recent study from our laboratory using recombinant full-length (encompassing the variable and constant domain) immunoglobulin light chains found a strong kinetic control of the protein unfolding for these proteins. In this study, we are extending our analysis by using urine-derived Bence Jones proteins (BJPs) from five patients with light chain (AL) amyloidosis and four patients with multiple myeloma (MM). We observed lower stability in ? proteins compared to ? proteins (for both MM and AL proteins) in agreement with previous studies. The kinetic component of protein stability is not a universal feature of BJPs and the hysteresis observed during refolding reactions could be attributed to the inability of the protein to refold all domains. The most stable proteins exhibited 3-state unfolding transitions. While these proteins do not refold reversibly, partial refolding shows 2-state partial refolding transitions, suggesting that one of the domains (possibly the variable domain) does not refold completely. Sequences were aligned with their respective germlines and the location and nature of the mutations were analyzed. The location of the mutations were analyzed and compared with the stability and amyloidogenic properties for the proteins in this study, increasing our understanding of light chain unfolding and amyloidogenic potential.

SUBMITTER: Blancas-Mejia LM

PROVIDER: S-EPMC5626661 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Kinetic stability and sequence/structure studies of urine-derived Bence-Jones proteins from multiple myeloma and light chain amyloidosis patients.

Blancas-Mejía Luis M LM Martin Emily B EB Williams Angela A Wall Jonathan S JS Ramirez-Alvarado Marina M

Biophysical chemistry 20170901

It is now accepted that the ability of a protein to form amyloid fibrils could be associated both kinetic and thermodynamic protein folding parameters. A recent study from our laboratory using recombinant full-length (encompassing the variable and constant domain) immunoglobulin light chains found a strong kinetic control of the protein unfolding for these proteins. In this study, we are extending our analysis by using urine-derived Bence Jones proteins (BJPs) from five patients with light chain ...[more]

PMID: 28916410

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Project description:Rationale & objectiveTest the feasibility of replacing 24-hour urine collection with a single voided urinary protein-creatinine ratio (UPCR) in patients with amyloid light-chain (AL) amyloidosis.Study designRetrospective study examining the correlation between a 24-hour urine measurement and UPCR at various proteinuria levels using a linear regression analysis with Pearson's correlation coefficient (r). We assessed how using these 2 different measurements would alter the diagnosis, staging, and kidney response assessment in patients with AL amyloidosis.Setting & participantsWe included 265 patients with systemic AL amyloidosis who visited the Amyloidosis Center at Boston University between July 2018-January 2020 and had proteinuria measurement by both methods on the same day.Tests compared24-hour urine collection for protein versus UPCR.ResultsThe correlation between 24-hour urine and UPCR was moderate in patients with proteinuria levels of 500-3,000 mg/day and >3,000 mg/day, with r values of 0.57 and 0.62, respectively. Replacing the 24-hour urine collection with UPCR changed kidney staging in 10% of the patients: 77% were reclassified to a worse kidney stage and 23% to a more favorable stage. The majority of changes (85%) in kidney staging occurred in the >3,000 mg/day cohort. There were 35 patients whose kidney response was assessed by concomitant 24-hour urine collection and UPCR with visits at least 6 months apart. Of these patients, 20% had discordance between the 24-hour urine collection and UPCR that changed their definition of organ response.LimitationsGiven the rarity of AL amyloidosis, our sample size is small and from a single referral center.ConclusionsAlthough the 24-hour urine collection is cumbersome, we continue to recommend it in patients with AL amyloidosis because replacing the 24-hour urine collection with UPCR would change kidney staging and organ response in 10%-20% of patients. In addition, the correlation between the 2 modalities was moderate at best in patients with nephrotic-range proteinuria.

Project description:BackgroundBence Jones proteinuria is a disorder that is defined by the excretion of monoclonal light-chain protein. About 15-20% of patients with multiple myeloma secrete monoclonal light chains only, without expression of the normal immunoglobulin heavy chain, which constitutes light-chain multiple myeloma. The definition, prevalence, and progression of these premalignant phases of light-chain multiple myeloma have not been fully characterised. We aimed to identify a subset of patients with idiopathic Bence Jones proteinuria who had a high risk of progression to light-chain multiple myeloma analogous to that seen in patients with smouldering multiple myeloma.MethodsIn this retrospective cohort study, we studied all patients seen at the Mayo Clinic (Rochester, MN, USA) within 30 days of diagnosis of idiopathic Bence Jones proteinuria between Jan 1, 1960, and June 30, 2004. Inclusion criteria were monoclonal light chain in the urine (≥0·2 g/24 h), absence of intact monoclonal immunoglobulin (M protein) in the serum, and no evidence of multiple myeloma, light-chain amyloidosis, or other related plasma-cell proliferative disorders. The primary endpoint was progression to symptomatic multiple myeloma or light-chain amyloidosis. We examined the cumulative probability of progression and the association of potential risk factors on progression rates to identify patients with a high risk of progression to multiple myeloma or light-chain amyloidosis.FindingsWe identified 101 patients with idiopathic Bence Jones proteinuria. During 901 total person-years of follow-up, 27 (27%) patients developed multiple myeloma and seven (7%) developed light-chain amyloidosis. The major risk factors for progression were amount of urinary excretion of M protein per 24 h, proportion of bone marrow plasma cells, presence of a markedly abnormal free-light-chain ratio (<0·01 or >100), and reduction of all three uninvolved immunoglobulins. Based on the risk of progression, monoclonal light-chain excretion of 0·5 g/24 h or greater or at least 10% bone marrow plasma cells, or both, in the absence of end-organ damage was used to define light-chain smouldering multiple myeloma. The cumulative probability of progression to active multiple myeloma or light-chain amyloidosis in patients with light-chain smouldering multiple myeloma was 27·8% (95% CI 14·2-39·2) at 5 years, 44·6% (27·9-57·4) at 10 years, and 56·5% (36·3-70·2) at 15 years.InterpretationLight-chain smouldering multiple myeloma as defined in this study is associated with a high risk of progression to symptomatic light-chain multiple myeloma, and this subset of patients needs careful observation and could benefit from clinical trials of early intervention.FundingJabbs Foundation (Birmingham, UK), US National Cancer Institute, and Henry J Predolin Foundation (Madison, WI, USA).

Dataset Information

Kinetic stability and sequence/structure studies of urine-derived Bence-Jones proteins from multiple myeloma and light chain amyloidosis patients.

Publications

Kinetic stability and sequence/structure studies of urine-derived Bence-Jones proteins from multiple myeloma and light chain amyloidosis patients.

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