The tropism of organ involvement in primary systemic amyloidosis: contributions of Ig VL germ line gene use and clonal plasma cell burden

Comenzo, Raymond L.; Zhang, Yana; Martínez, Carmen Rodríguez; Osman, Keren; Herrera, Guillermo A.

doi:10.1182/blood.v98.3.714

Cited by 254 publications

(239 citation statements)

References 33 publications

(42 reference statements)

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“…To this same end, Comenzo et al 8 very recently reported the sequencing results from 60 patients with amyloidosis (48 of the type). The authors 8 were able to establish an association between 6a light chains and major or exclusive amyloid kidney involvement, an association that was further substantiated by amyloid formation from VI light chains cultured in a human mesangial cell model. In the present study, we confirmed this seminal observation 8 : 8 of 11 VI light chains (P ϭ .019) were isolated from patients with predominant kidney involvement at diagnosis.…”

Section: Figure 5 Somatic Mutations In Amyloid and Polyclonal V Regimentioning

confidence: 99%

“…In addition, although 3r patients apparently present amyloid infiltration of various organs, this study confirms the previous observation that 6a light chains preferentially generate amyloid in the kidney. 8 These findings may have relevance for a better comprehension of the mechanisms underlying amyloidogenicity of light chains. The fact that just 2 genes are highly overrepresented in amyloidosis will help in designing DNA-based vaccine approaches as well as molecules capable of interfering with the amyloid deposition process.…”

Section: Figure 5 Somatic Mutations In Amyloid and Polyclonal V Regimentioning

confidence: 99%

“…The reasons for the diversity in organ distribution of AL amyloidosis are unknown. Very recently, Comenzo et al 8 documented that VI light chains were more likely to be found in patients with dominant renal involvement at diagnosis, raising the possibility that, at least in some instances, the diverse organ tropism of amyloid light chains may be influenced by VL gene usage.…”

Section: Introductionmentioning

confidence: 99%

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Analysis of Vλ-Jλ expression in plasma cells from primary (AL) amyloidosis and normal bone marrow identifies 3r(λIII) as a new amyloid-associated germline gene segment

Perfetti

Casarini

Palladini

et al. 2002

Blood

148

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Primary (AL) amyloidosis is a plasma cell dyscrasia characterized by extracellular deposition of monoclonal light-chain variable region (V) fragments in the form of amyloid fibrils. Light-chain amyloid is rare, and it is not fully understood why it occurs in only a fraction of patients with a circulating monoclonal component and why it typically associates with isotype and VI family light-chain proteins. To provide insights into these issues, we obtained complete nucleotide sequences of monoclonal V regions from 55 consecutive unselected cases of primary amyloidosis and the results were compared with the light-chain expression profile of polyclonal marrow plasma cells from 3 healthy donors (a total of 264 sequences). We demonstrated that: (1) the III family is the most frequently used both in amyloidosis (47%) and in polyclonality (43%); (2) both conditions are characterized by gene restriction; (3) a very skewed repertoire is a feature of amyloidosis, because just 2 germline genes belonging to the III and VI families, namely 3r (22% of cases, III) and 6a (20%, VI), contributed equally to encode 42% of amyloid V regions; (4) these same 2 gene segments have a strong association with amyloidosis if their prevalences are compared with those in polyclonal conditions (3r, 8.3%, P ‫؍‬ .024; 6a, 2.3%, P ‫؍‬ .0008, 2 test); (5) the J 2/3 segment, encoding the fourth framework region, appears to be slightly overrepresented in AL (83% versus 67%, P ‫؍‬ .03), and this might be related to preferential J 2/3 rearrangement in amyloid (11 of 12 cases) versus polyclonal 3r light chains (13 of 22 cases). These findings demonstrate that V -J expression is more restricted in plasma cells from amyloidosis than from polyclonal bone marrow and identify 3r as a new disease-associated gene segment. Overusage of just 2 gene segments, 3r and 6a, can thus account for the light-chain overrepresentation typical of this disorder. (Blood. 2002;100: 948-953)

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Section: Figure 5 Somatic Mutations In Amyloid and Polyclonal V Regimentioning

confidence: 99%

Section: Figure 5 Somatic Mutations In Amyloid and Polyclonal V Regimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Analysis of Vλ-Jλ expression in plasma cells from primary (AL) amyloidosis and normal bone marrow identifies 3r(λIII) as a new amyloid-associated germline gene segment

Perfetti

Casarini

Palladini

et al. 2002

Blood

148

View full text Add to dashboard Cite

show abstract

“…18,19 Furthermore, the variable region of the light chain probably determines the specific type of renal damage that a light chain can cause. Both lambda and kappa light chains are nephrotoxic, but lambda light chains are more frequently involved in the formation of amyloid than kappa, 20 and kappa are more frequently involved in other types of renal damage, such as LCDD 21 and acquired adult Fanconi's syndrome. 22 Cast formation is not the only pathophysiologic mechanism in myeloma kidney.…”

Section: Pathogenesismentioning

confidence: 99%

Pathogenesis and treatment of renal failure in multiple myeloma

et al. 2008

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Renal failure is a frequent complication in patients with multiple myeloma (MM) that causes significant morbidity. In the majority of cases, renal impairment is caused by the accumulation and precipitation of light chains, which form casts in the distal tubules, resulting in renal obstruction. In addition, myeloma light chains are also directly toxic on proximal renal tubules, further adding to renal dysfunction. Adequate hydration, correction of hypercalcemia and hyperuricemia and antimyeloma therapy should be initiated promptly. Recovery of renal function has been reported in a significant proportion of patients treated with conventional chemotherapy, especially when high-dose dexamethasone is also used. Severe renal impairment and large amount of proteinuria are associated with a lower probability of renal recovery. Novel agents, such as thalidomide, bortezomib and lenalidomide, have significant activity in pretreated and untreated MM patients. Although there is limited experience with thalidomide and lenalidomide in patients with renal failure, data suggest that bortezomib may be beneficial in this population. Clinical studies that have included newly diagnosed and refractory patients indicate that bortezomib-based regimens may result in rapid reversal of renal failure in up to 50% of patients and that full doses of bortezomib can be administered without additional toxicity.

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“…To assess the role of k-light chain variable region germline gene usage in our patients, we amplified and sequenced the dominant k-light chain variable germline gene in the baseline marrow cells of four patients using methods described previously. 19,20 Treatment All patients received initial therapy for multiple myeloma prior to undergoing their consolidation with HDM and auto-SCT. The goal of initial therapy in multiple myeloma is the achievement of a low tumor burden prior to the transplant.…”

Section: Patient Selection and Evaluationmentioning

confidence: 99%

High-dose melphalan and auto-SCT in patients with monoclonal Ig deposition disease

Hassoun

Flombaum

D’Agati

et al. 2008

Bone Marrow Transplant

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The tropism of organ involvement in primary systemic amyloidosis: contributions of Ig VL germ line gene use and clonal plasma cell burden

Cited by 254 publications

References 33 publications

Analysis of Vλ-Jλ expression in plasma cells from primary (AL) amyloidosis and normal bone marrow identifies 3r(λIII) as a new amyloid-associated germline gene segment

Analysis of Vλ-Jλ expression in plasma cells from primary (AL) amyloidosis and normal bone marrow identifies 3r(λIII) as a new amyloid-associated germline gene segment

Pathogenesis and treatment of renal failure in multiple myeloma

High-dose melphalan and auto-SCT in patients with monoclonal Ig deposition disease

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