Assay to rapidly screen for immunoglobulin light chain glycosylation: a potential path to earlier AL diagnosis for a subset of patients

Kumar, Sanjay; Murray, David; Dasari, Surendra; Milani, Paolo; Barnidge, David R.; Madden, Benjamin J.; Kourelis, Taxiarchis; Arendt, Bonnie K.; Merlini, Giampaolo; Ramı́rez-Alvarado, Marina; Dispenzieri, Angela

doi:10.1038/s41375-018-0194-x

Cited by 58 publications

(60 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This study confirms that early mortality continues to be a primary reason for treatment failure in APL patients, and is significantly higher in population-based studies than patients enrolled in clinical trials. 2 Older age was a negative prognostic factor, though this group also experienced an improvement in early mortality over time. This may be due to newer strategies that depend on treatments that have more favorable toxicity profiles like arsenic trioxide.…”

Section: Complications and Early Mortality In Patients With Acute Promentioning

confidence: 87%

MASS‐FIX may allow identification of patients at risk for light chain amyloidosis before the onset of symptoms

et al. 2018

Self Cite

View full text Add to dashboard Cite

Section: Complications and Early Mortality In Patients With Acute Promentioning

confidence: 87%

MASS‐FIX may allow identification of patients at risk for light chain amyloidosis before the onset of symptoms

et al. 2018

Self Cite

View full text Add to dashboard Cite

“… 14 Post translational modifications are also important; it has been recognized that the clonal light chains in amyloidosis show high levels of N-glycosylation and dimerization. 15 , 16 …”

Section: Biology Of Al Amyloidosismentioning

confidence: 99%

Systemic AL Amyloidosis: Current Approaches to Diagnosis and Management

Fotiou

Dimopoulos

2020

HemaSphere

View full text Add to dashboard Cite

AL amyloidosis is characterized by a low-level expansion of an indolent, small plasma cell clone that produces amyloidogenic light chains. Amyloid aggregates or preceding intermediaries cause direct cell damage through their proteotoxicity, and amyloid deposits distort tissue architecture, and, eventually, lead to organ impairment. It is a rare, underdiagnosed disease with a diverse clinical presentation depending on the organ tropism of the amyloid fibrils; cardiac and renal involvement is most common, but any organ can be affected, excluding the central nervous system. A high level of awareness and a systematic approach using newly emerging screening biomarkers is required to achieve early diagnosis. Management should be multidisciplinary as supportive management tailored to management of organ dysfunction is paramount to survival and minimization of treatment-associated toxicity. The initial therapeutic aim is to rapidly eliminate the clonal plasma cell that produces the circulating amyloid precursor and achieve a complete hematologic response, and if possible with undetectable minimal residual disease as assessed by next-generation methods (flow and sequencing), with minimal toxicity. Treatment is tailored to the initial risk assessment of the patients. Treatments are based on regimens adapted from the expanding options that are available for multiple myeloma patients and hematological response rates have improved. Organ response rates are strongly associated with deeper hematologic response but usually lag behind hematological response and are also dependent on the initial organ function reserve. Agents directed against the amyloid deposits have been explored to aid amyloid clearance and improve organ function, but data are still negative.

show abstract

“…Recent interesting data have emerged from the study of post-translational modifications of monoclonal light chains from the serum of patients with AL amyloidosis or other plasma cell disorders. In particular, the use of mass spectrometry on immunopurified light chains from patients’ serum has identified distinctive M protein mass distributions patterns possibly indicating N-glycosylation of monoclonal light chains in 33 and 10.2% of patients with AL-κ and AL-λ amyloidosis, compared to 3.7 and 4.9% in patients with non-AL monoclonal gammopathies of κ and λ type, respectively ( Kumar et al., 2019 ). Subsequent analyses in a subset of cases involving enzymatic deglycosylation and mass spectrometric analysis confirmed the presence of N-glycosylation in the analysed monoclonal light chains ( Kumar et al., 2019 ).…”

Section: Reduction/elimination Of the Amyloid-forming Protein May Delmentioning

confidence: 99%

“…In particular, the use of mass spectrometry on immunopurified light chains from patients’ serum has identified distinctive M protein mass distributions patterns possibly indicating N-glycosylation of monoclonal light chains in 33 and 10.2% of patients with AL-κ and AL-λ amyloidosis, compared to 3.7 and 4.9% in patients with non-AL monoclonal gammopathies of κ and λ type, respectively ( Kumar et al., 2019 ). Subsequent analyses in a subset of cases involving enzymatic deglycosylation and mass spectrometric analysis confirmed the presence of N-glycosylation in the analysed monoclonal light chains ( Kumar et al., 2019 ). These observations are in line with previous studies on a limited number of amyloidogenic light chains showing N-glycosylation as a post-translational modification detected in a subset of cases ( Stevens, 2000 ).…”

Section: Reduction/elimination Of the Amyloid-forming Protein May Delmentioning

confidence: 99%

“…These observations are in line with previous studies on a limited number of amyloidogenic light chains showing N-glycosylation as a post-translational modification detected in a subset of cases ( Stevens, 2000 ). As mass spectrometry analysis is an emerging area for the screening of M proteins, the identification of potential N-glycosylation in monoclonal light chain may help identifying subjects at higher risk of developing AL amyloidosis ( Kumar et al., 2019 ).…”

Section: Reduction/elimination Of the Amyloid-forming Protein May Delmentioning

confidence: 99%

See 1 more Smart Citation

Treating Protein Misfolding Diseases: Therapeutic Successes Against Systemic Amyloidoses

Nevone

Merlini

2020

Front. Pharmacol.

Self Cite

View full text Add to dashboard Cite

Misfolding and extracellular deposition of proteins is the hallmark of a heterogeneous group of conditions collectively termed protein misfolding and deposition diseases or amyloidoses. These include both localized (e.g. Alzheimer’s disease, prion diseases, type 2 diabetes mellitus) and systemic amyloidoses. Historically regarded as a group of maladies with limited, even inexistent, therapeutic options, some forms of systemic amyloidoses have recently witnessed a series of unparalleled therapeutic successes, positively impacting on their natural history and sometimes even on their incidence. In this review article we will revisit the most relevant of these accomplishments. Collectively, current evidence converges towards a crucial role of an early and conspicuous reduction or stabilization of the amyloid-forming protein in its native conformation. Such an approach can reduce disease incidence in at risk individuals, limit organ function deterioration, promote organ function recovery, improve quality of life and extend survival in diseased subjects. Therapeutic success achieved in these forms of systemic amyloidoses may guide the research on other protein misfolding and deposition diseases for which effective etiologic therapeutic options are still absent.

show abstract

Assay to rapidly screen for immunoglobulin light chain glycosylation: a potential path to earlier AL diagnosis for a subset of patients

Cited by 58 publications

References 15 publications

MASS‐FIX may allow identification of patients at risk for light chain amyloidosis before the onset of symptoms

MASS‐FIX may allow identification of patients at risk for light chain amyloidosis before the onset of symptoms

Systemic AL Amyloidosis: Current Approaches to Diagnosis and Management

Treating Protein Misfolding Diseases: Therapeutic Successes Against Systemic Amyloidoses

Contact Info

Product

Resources

About