Infiltrative Nonamyloidotic Monoclonal Immunoglobulin Light Chain Cardiomyopathy: An Underappreciated Manifestation of Plasma Cell Dyscrasias

Cardiology ◽  
2000 ◽  
Vol 93 (4) ◽  
pp. 220-228 ◽  
Author(s):  
Joel N. Buxbaum ◽  
Elizabeth M. Genega ◽  
Piotr Lazowski ◽  
Asok Kumar ◽  
Paul A. Tunick ◽  
...  
Keyword(s):  
Plasma Cell ◽  
Light Chain ◽  
Immunoglobulin Light Chain ◽  
Monoclonal Immunoglobulin ◽  
Plasma Cell Dyscrasias

scholarly journals Immunoglobulin light chain amyloidosis is diagnosed late in patients with preexisting plasma cell dyscrasias

2014 ◽  
Vol 89 (11) ◽  
pp. 1051-1054 ◽  
Author(s):  
Taxiarchis V. Kourelis ◽  
Shaji K. Kumar ◽  
Ronald S. Go ◽  
Prashant Kapoor ◽  
Robert A. Kyle ◽  
...  
Keyword(s):  
Plasma Cell ◽  
Light Chain ◽  
Immunoglobulin Light Chain ◽  
Light Chain Amyloidosis ◽  
Plasma Cell Dyscrasias ◽  
Immunoglobulin Light Chain Amyloidosis

scholarly journals Genetic pathogenesis of immunoglobulin light chain amyloidosis: basic characteristics and clinical applications

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Linchun Xu ◽  
Yongzhong Su
Keyword(s):  
Plasma Cell ◽  
Light Chain ◽  
Amyloid Fibril ◽  
Treatment Modalities ◽  
Driver Gene ◽  
Immunoglobulin Light Chain ◽  
Disease Evolution ◽  
Genetic Aberrations ◽  
Light Chain Amyloidosis ◽  
Immunoglobulin Light Chain Amyloidosis

AbstractImmunoglobulin light chain amyloidosis (AL) is an indolent plasma cell disorder characterized by free immunoglobulin light chain (FLC) misfolding and amyloid fibril deposition. The cytogenetic pattern of AL shows profound similarity with that of other plasma cell disorders but harbors distinct features. AL can be classified into two primary subtypes: non-hyperdiploidy and hyperdiploidy. Non-hyperdiploidy usually involves immunoglobulin heavy chain translocations, and t(11;14) is the hallmark of this disease. T(11;14) is associated with low plasma cell count but high FLC level and displays distinct response outcomes to different treatment modalities. Hyperdiploidy is associated with plasmacytosis and subclone formation, and it generally confers a neutral or inferior prognostic outcome. Other chromosome abnormalities and driver gene mutations are considered as secondary cytogenetic aberrations that occur during disease evolution. These genetic aberrations contribute to the proliferation of plasma cells, which secrete excess FLC for amyloid deposition. Other genetic factors, such as specific usage of immunoglobulin light chain germline genes and light chain somatic mutations, also play an essential role in amyloid fibril deposition in AL. This paper will propose a framework of AL classification based on genetic aberrations and discuss the amyloid formation of AL from a genetic aspect.

Kidney disease and plasma cell dyscrasias: ambiguous cases solved by serum free light chain dimerization analysis

2019 ◽  
Vol 23 (6) ◽  
pp. 763-772
Author(s):  
Olga Kukuy ◽  
Batia Kaplan ◽  
Sizilia Golderman ◽  
Alexander Volkov ◽  
Adrian Duek ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Plasma Cell ◽  
Light Chain ◽  
Free Light Chain ◽  
Serum Free ◽  
Serum Free Light Chain ◽  
Plasma Cell Dyscrasias

scholarly journals Kidney disease associated with plasma cell dyscrasias

Blood ◽  
2010 ◽  
Vol 116 (9) ◽  
pp. 1397-1404 ◽  
Author(s):  
Eliot C. Heher ◽  
Nelson B. Goes ◽  
Thomas R. Spitzer ◽  
Noopur S. Raje ◽  
Benjamin D. Humphreys ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Plasma Cell ◽  
Molecular Mechanisms ◽  
Kidney Injury ◽  
Light Chains ◽  
Free Light Chains ◽  
Monoclonal Immunoglobulin ◽  
Plasma Cell Dyscrasias ◽  
Made In

Plasma cell dyscrasias are frequently encountered malignancies often associated with kidney disease through the production of monoclonal immunoglobulin (Ig). Paraproteins can cause a remarkably diverse set of pathologic patterns in the kidney and recent progress has been made in explaining the molecular mechanisms of paraprotein-mediated kidney injury. Other recent advances in the field include the introduction of an assay for free light chains and the use of novel antiplasma cell agents that can reverse renal failure in some cases. The role of stem cell transplantation, plasma exchange, and kidney transplantation in the management of patients with paraprotein-related kidney disease continues to evolve.

Knockdown of Pathologic Immuoglobulin Light Chain Protein by Small Interfering RNA Molecules.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4407-4407
Author(s):  
Jonathan E Phipps ◽  
James S Foster ◽  
Daniel P Kestler ◽  
Robert Donnell ◽  
Alan Solomon ◽  
...  
Keyword(s):  
Cell Line ◽  
Plasma Cell ◽  
Light Chain ◽  
Small Interfering Rna ◽  
Mrna Levels ◽  
Light Chain Deposition Disease ◽  
Rna Molecules ◽  
Plasma Cell Dyscrasias ◽  
Rpmi 8226 ◽  
Interfering Rna

Abstract Abstract 4407 Introduction A major contributing factor to the morbidity and mortality of patients with plasma cell dyscrasias (i.e., light chain deposition disease, light chain amyloidosis (AL), etc.) is the overproduction and deposition of immunoglobulin light chain (LC) protein. Accumulation of insoluble fibrillar or amorphous aggregates within vital organs, particularly the kidneys, contributes to progressive loss of function and failure. Recent reports have shown that reducing levels of precursor LC proteins by 50% correlated with improved prognosis in patients with AL. Current therapies to suppress the production of monoclonal free LC rely on conventional or high dose myeloablative chemotherapeutic intervention. These therapies carry inherent risk and may not be appropriate in every situation, thus there is a need to employ alternative or adjuvant therapeutic approaches. To this end, we have investigated the ability of small interfering RNA molecules to decrease production of LC mRNA and protein secretion in both a synthetic and naturally occurring myeloma cell line. We report here that exposure of these lines to small interfering RNA (siRNA) oligonucleotides inhibited LC production in a specific and non-cytotoxic manner. Methods SP2/O mouse myeloma cells were stably transfected with a construct encoding a human λ6 LC protein (Wil) and designated SP2/O-1 for this study. The human λ2 producing cell line RPMI 8226 was purchased from ATCC. For both lines, LC mRNA was sequenced and used to design siRNA molecules targeting the V-, J-, or C-region of the LC. Cells were cultured for 1-3 d with sequence-specific siRNA, sham siRNA, or with media alone after which time LC mRNA levels were assessed by real-time PCR, and cellular or secreted LC protein concentrations were measured using flow cytometry or ELISA, respectively. Results Treatment with siRNA was well tolerated and no significant reduction in cell viability was observed in either the SP2/O-1 or RPMI 8226 cells at any of the timepoints assayed. Exposure of either SP2/O-1 or 8226 cells to siRNAs targeting the LC resulted in reductions of mRNA as compared to sham siRNA-treated controls. Flow cytometric analysis of 8226 cells immunostained with anti-LC antibodies at 48 h post transfection, indicated that ∼63% and 83% of the total cell number contained reduced amounts of cytoplasmic LC following treatment with V-, or C- region-specific siRNA, respectively. The 8226 LC protein was also significantly reduced by 20-60% in culture supernatants over the 72h period in cells exposed to experimental siRNAs as compared with sham-treated cells. Similarly, treating the SP2/O-1 cells with siRNAs led to significant (20-52%; P < 0.05) reductions in secreted LC Wil over 72 h as compared to sham-siRNA treatments. Conclusions We demonstrate here that siRNA provides a viable option for preventing the synthesis and thus secretion of pathologic LC protein using two cell lines, and that this reduction is carried out in a specific and non-cytotoxic manner. These results provide support for the potential use of siRNA to decrease the secretion of pathologic LC proteins in patients diagnosed with plasma cell dyscrasias. Our future goal will be to evaluate the action of siRNAs on LC production in vivo using a murine model of the disease. Disclosures: No relevant conflicts of interest to declare.

Frequency of Amyloid Subtyping Among Patients with Immunoglobulin Light-Chain Amyloidosis Referred for High-Dose Chemotherapy and Autologous Stem Cell Transplant

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5601-5601
Author(s):  
Andrew J. Cowan ◽  
David G. Coffey ◽  
Teresa S. Hyun ◽  
Pamela S. Becker ◽  
Damian J. Green ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Plasma Cell ◽  
Light Chain ◽  
Congo Red ◽  
Plasma Cell Dyscrasia ◽  
High Dose ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Immunoglobulin Light Chain ◽  
Organ Systems

Abstract Background: The amyloidoses comprise a heterogeneous group of diseases characterized by misfolding of amyloidogenic proteins and subsequent deposition as amyloid fibrils. To date, over 30 proteins are known to be amyloidogenic (Sipe Amyloid 2014). Immunoglobulin light chain (AL) amyloidosis, a plasma cell dyscrasia, is the most common subtype. The standard diagnostic algorithm in AL amyloidosis is to obtain a biopsy of a clinically involve organ, and once Congo red positivity is confirmed, perform subtyping analyses with immunohistochemistry or mass spectrometry. Accurate subtyping of amyloidosis is essential to appropriate treatment, as misdiagnosis occurs in up to 10% of patients and may lead to inappropriate administration of chemotherapy (Comenzo Blood 2006; Lachmann NEJM 2002). We sought to determine the patterns of amyloid subtyping among patients with a diagnosis of AL amyloidosis referred to a tertiary referral center for HDM/SCT. Methods: Sequential patients with confirmed amyloidosis, age ≥ 18 years who underwent HDM/SCT between 2001 and 2014 at the Fred Hutchinson Cancer Research Center and University of Washington Medical Center were eligible. Presence of a Congo red-positive biopsy for each patient referred for transplant was confirmed and the pathology reports and medical records were reviewed to determine if subtyping was performed, and which modality was used. Results: Fifty-one patients with AL amyloidosis were referred for transplant; of these, 45 proceeded with HDM/SCT. The organ systems most commonly involved were renal in 34/51, and gastrointestinal in 5/51. Of the biopsies, subtyping was performed in 35 (68.6%), and no subtyping was performed in 16 patients (31.3%). Immunofluorescence was the most common modality used for subtyping in 33 biopsies (94.2%) and laser capture/mass spectrometry (LC/MS) was used in 2 patients (5.7%). All patients had evidence of a clonal plasma cell dyscrasia by bone marrow biopsy and peripheral blood testing. Of the patients without subtyping, 8 (50%) were diagnosed before 2008. Discussion: Misdiagnosis of amyloidosis due to a lack of appropriate subtyping is a well-described and ongoing problem for patients with amyloidosis. These data suggest that definitive subtyping is still not routinely performed in the evaluation of amyloidosis. At our center, efforts to standardize the evaluation of Congo-red positive biopsies using definitive typing are underway. Disclosures Gopal: Seattle Genetics: Research Funding.

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