Dataset Information

Calreticulin expression in the clonal plasma cells of patients with systemic light-chain (AL-) amyloidosis is associated with response to high-dose melphalan.

ABSTRACT: In high doses with stem-cell transplantation, melphalan is an effective but toxic therapy for patients with systemic light-chain (AL-) amyloidosis, a protein deposition and monoclonal plasma cell disease. Melphalan can eliminate the indolent clonal plasma cells that cause the disease, an achievement called a complete response. Such a response is usually associated with extended survival, while no response (a less than 50% reduction) is not. Gene-expression studies and a stringently supervised analysis identified calreticulin as having significantly higher expression in the pretreatment plasma cells of patients with systemic AL-amyloidosis who then had a complete response to high-dose melphalan. Calreticulin is a pleiotropic calcium-binding protein found in the endoplasmic reticulum and the nucleus whose overexpression is associated with increased sensitivity to apoptotic stimuli. Real-time PCR and immunohistochemical staining also showed that expression of calreticulin was higher in the plasma cells of those with a complete response. Furthermore, wild-type murine embryonic fibroblasts were significantly more sensitive to melphalan than calreticulin knock-out murine embryonic fibroblasts. These data have important implications for understanding the activity of melphalan in plasma-cell diseases and support further investigation of calreticulin and its modulation in patients with systemic AL-amyloidosis receiving high-dose melphalan.

SUBMITTER: Zhou P

PROVIDER: S-EPMC2200859 | biostudies-literature | 2008 Jan

REPOSITORIES: biostudies-literature

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Calreticulin expression in the clonal plasma cells of patients with systemic light-chain (AL-) amyloidosis is associated with response to high-dose melphalan.

Zhou Ping P Teruya-Feldstein Julie J Lu Ping P Fleisher Martin M Olshen Adam A Comenzo Raymond L RL

Blood 20071102 2

In high doses with stem-cell transplantation, melphalan is an effective but toxic therapy for patients with systemic light-chain (AL-) amyloidosis, a protein deposition and monoclonal plasma cell disease. Melphalan can eliminate the indolent clonal plasma cells that cause the disease, an achievement called a complete response. Such a response is usually associated with extended survival, while no response (a less than 50% reduction) is not. Gene-expression studies and a stringently supervised an ...[more]

PMID: 17982021

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Project description:Immunoglobulin light-chain amyloidosis (AL) is a rare clonal plasma cell (PC) disorder that remains largely incurable. AL and multiple myeloma (MM) share the same cellular origin, but while knowledge about MM PC biology has improved significantly, the same does not apply for AL. Here, we undertook an integrative phenotypic, molecular, and genomic approach to study clonal PCs from 22 newly-diagnosed AL patients. Through principal-component-analysis, we demonstrated highly overlapping phenotypic profiles between AL and MGUS or MM patients. However, in contrast to MM, highly-purified FACSs-sorted clonal PCs in AL (n=9/22) show virtually normal transcriptomes with only 68 deregulated genes as compared to normal PCs, including a few tumor suppressor (CDH1, RCAN) and pro-apoptotic (GLIPR1, FAS) genes. Notwithstanding, clonal PCs in AL (n=11/22) were genomically unstable with a median of 9 copy-number-abnormities (CNAs) per case; many of which similar to those found in MM. Whole-exome sequencing (WES) was performed in three AL patients and revealed a median of 10 non-recurrent mutations per case. Altogether, we showed that although clonal PCs in AL display phenotypic and CNA profiles similar to MM, their transcriptome is remarkably similar to that of normal PCs. First-ever WES revealed the lack of a unifying mutation in AL A total of 22 patients with confirmed diagnosis of AL based on the presence of amyloid-related systemic syndrome, positive amyloid tissue staining with Congo red, and evidence of PC clonality were studied. Samples were collected after informed consent was given, in accordance with local ethical committee guidelines and the Helsinki Declaration. GEP was performed in 9/22 AL cases with adequate RNA extracted from FACS-purified clonal PCs according to patient-specific aberrant phenotypes, and compared to that of normal PCs from 5 healthy individuals (FACSAriaIIb, BDB; â¥95% purity). RNA was hybridized to the Human Gene 1.0 ST Array (Affymetrix, Santa Clara, CA, USA) and normalization was carried using the expression console (Affymetrix) with the RMA algorithm which includes background correction, normalization and calculation of expression values (log2). Differentially expressed genes between classes were identified using the Significant Analysis of Microarrays (SAM) algorithm (http://www-stat.standford.edu/-tibs/SAM), and significant genes were selected based on the lowest q-value (<10-5).

Project description:Immunoglobulin light-chain amyloidosis (AL) is a rare clonal plasma cell (PC) disorder that remains largely incurable. AL and multiple myeloma (MM) share the same cellular origin, but while knowledge about MM PC biology has improved significantly, the same does not apply for AL. Here, we undertook an integrative phenotypic, molecular, and genomic approach to study clonal PCs from 22 newly-diagnosed AL patients. Through principal-component-analysis, we demonstrated highly overlapping phenotypic profiles between AL and MGUS or MM patients. However, in contrast to MM, highly-purified FACSs-sorted clonal PCs in AL (n=9/22) show virtually normal transcriptomes with only 68 deregulated genes as compared to normal PCs, including a few tumor suppressor (CDH1, RCAN) and pro-apoptotic (GLIPR1, FAS) genes. Notwithstanding, clonal PCs in AL (n=11/22) were genomically unstable with a median of 9 copy-number-abnormities (CNAs) per case; many of which similar to those found in MM. Whole-exome sequencing (WES) was performed in three AL patients and revealed a median of 10 non-recurrent mutations per case. Altogether, we showed that although clonal PCs in AL display phenotypic and CNA profiles similar to MM, their transcriptome is remarkably similar to that of normal PCs. First-ever WES revealed the lack of a unifying mutation in AL A total of 22 patients with confirmed diagnosis of AL based on the presence of amyloid-related systemic syndrome, positive amyloid tissue staining with Congo red, and evidence of PC clonality were studied. Samples were collected after informed consent was given, in accordance with local ethical committee guidelines and the Helsinki Declaration. Genome-wide detection of CNAs and copy-number neutral loss-of-heterozygosity (LOH) were investigated using the Cytoscan 750K platform (Affymetrix) in 11/22 cases with adequate DNA extracted from FACS-sorted clonal PCs and paired T-lymphocytes. The AGCC and ChAS software programs (Affymetrix) were used for data analysis as described elsewhere. CNAs were reported when the three following criteria were met: â¥25 consecutive imbalanced markers per segment; â¥100Kb minimum genomic size and; <50% overlap with paired control DNA and/or genomic variants of Toronto DB (DGV). Only CNN-LOH larger that 5Mb, with â¥25 consecutive imbalanced markers per segment, and <50% overlap with patient-paired CNAs were considered.

Dataset Information

Calreticulin expression in the clonal plasma cells of patients with systemic light-chain (AL-) amyloidosis is associated with response to high-dose melphalan.

Publications

Calreticulin expression in the clonal plasma cells of patients with systemic light-chain (AL-) amyloidosis is associated with response to high-dose melphalan.

Similar Datasets

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