Fibromodulin, an extracellular matrix protein: characterization of its unique gene and protein expression in B-cell chronic lymphocytic leukemia and mantle cell lymphoma

Mikaelsson, Eva; Daneshmanesh, Amir Hossein; Lüppert, Alfred; Jeddi-Tehrani, Mahmood; Rezvany, Mohammad-Reza; Sharifian, Ramazan Ali; Safaie, Reza; Roohi, Azam; Österborg, Anders; Shokri, Fazel; Mellstedt, Håkan; Rabbani, Hodjattallah

doi:10.1182/blood-2004-10-3941

Cited by 56 publications

(59 citation statements)

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“…Previous reports suggest that expression of FMOD in hematological malignancies seems to be exclusive for CLL and mantle cell lymphoma. 34,35 In contrast, MARCKS, a gene implicated in suppression of proliferation, was upregulated in WM. 36 Genes exclusively deregulated in PC from MM but with a similar expression profile in PC from WM and NPC Again, using a stringent FDR, a total of 42 genes were identified as genes exclusively deregulated in PC from MM (MM-PC), although they had the same expression profile in PC from WM (WM-PC) and normal PC (Table 3).…”

Section: Resultsmentioning

confidence: 97%

Gene expression profiling of B lymphocytes and plasma cells from Waldenström's macroglobulinemia: comparison with expression patterns of the same cell counterparts from chronic lymphocytic leukemia, multiple myeloma and normal individuals

et al. 2007

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The tumoral clone of Waldenströ m's macroglobulinemia (WM) shows a wide morphological heterogeneity, which ranges from B lymphocytes (BL) to plasma cells (PC). By means of genomewide expression profiling we have been able to identify genes exclusively deregulated in BL and PC from WM, but with a similar expression pattern in their corresponding cell counterparts from chronic lymphocytic leukemia (CLL) and multiple myeloma (MM), as well as normal individuals. The differentially expressed genes have important functions in B-cell differentiation and oncogenesis. Thus, two of the genes downregulated in WM-BL were IL4R, which plays a relevant role in CLL B-cell survival, and BACH2, which participates in the development of class-switched PC. Interestingly, one of the upregulated genes in WM-BL was IL6. A set of four genes was able to discriminate clonal BL from WM and CLL: LEF1 (WNT/b-catenin pathway), MARCKS, ATXN1 and FMOD. We also found deregulation of genes involved in plasma cell differentiation such as PAX5, which was overexpressed in WM-PC, and IRF4 and BLIMP1, which were underexpressed. In addition, three of the target genes activated by PAX5 -CD79, BLNK and SYK -were upregulated in WM-PC. In summary, these results indicate that both PC and BL from WM are genetically different from the MM and CLL cell counterpart.

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Section: Resultsmentioning

confidence: 97%

Gene expression profiling of B lymphocytes and plasma cells from Waldenström's macroglobulinemia: comparison with expression patterns of the same cell counterparts from chronic lymphocytic leukemia, multiple myeloma and normal individuals

et al. 2007

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“…Recent findings in mouse leukemia revealed nonrandom DNA methylation in a highly ordered manner and assumed to play a central role for the malignant phenotype. 23 Further studies are needed to characterize over-expressed genes in vicinity of the ROR1 locus similar to what has been observed for the fibromodulin locus, 13 which may lead to the identification of other over-expressed genes on chromosome 1 in CLL. This is in accordance with our findings using FISH, which did not reveal any rearrangements in the ROR1 locus indicating that the expression of Ror1 is not related to genomic aberrations but may be due to epigenetic regulation.…”

Section: Discussionmentioning

confidence: 99%

“…Real-Time quantitative polymerase chain reaction (PCR) was performed as described earlier. 13 Sequencing of clonal immunoglobulin V(D)J rearrangements and ROR1 Amplification of the immunoglobulin V(D)J rearrangements was performed by PCR using cDNA from PBMC, consensus VH family primers as sense and constant l chain primer as antisense. The method has been described in details previously.…”

Section: Rt-pcr and Rt-qpcr Amplification Of Ror1mentioning

confidence: 99%

Ror1, a cell surface receptor tyrosine kinase is expressed in chronic lymphocytic leukemia and may serve as a putative target for therapy

Daneshmanesh

Mikaelsson

Jeddi‐Tehrani

et al. 2008

Intl Journal of Cancer

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Gene profiling studies of patients with chronic lymphocytic leukemia (CLL) has revealed increased expression of Ror1, a cell surface receptor tyrosine kinase. The aim of present study was to analyze gene and protein expression of Ror1 in CLL cells and normal blood leukocytes. Gene expression analysis reverse transcriptionpolymerase chain reaction of ROR1 revealed that all patients with CLL (n 5 100) spontaneously expressed ROR1 mRNA whereas enriched blood B and T cells as well as granulocytes from healthy donors (n 5 10) were negative. A strong nonphysiological activation signal (PMA/ionomycin) was required to induce expression in vitro in normal lymphocytes. Major genomic aberrations (mutations or truncation) of ROR1 were not observed. Protein expression was analyzed by Western blot using a panel of polyclonal anti-Ror antibodies as well as flow cytometry. Blood lymphocytes from 18/18 CLL patients, but none of the 10 healthy donors, expressed surface Ror1. The majority of CLL cells exhibited Ror1 surface expression (71% mean; range 36-92%) with a mean fluorescence intensity (MFI) of 20 (range 10-45). The corresponding MFI of CD19 on CLL cells was 26 (range 9-48). There was no difference in the Ror1 protein expression comparing IgVH mutated and unmutated cases as well as progressive and nonprogressive CLL patients. Two different variants of the Ror1 protein, 105 and 130 kDa, were identified. The Ror1 protein expression in patients with CLL but not in normal leukocytes merits further studies of its role in the pathobiology of CLL, which may provide a basis for development of Ror1 directed targeted therapy. ' 2008 Wiley-Liss, Inc. Key words: B-CLL; tyrosine kinase receptors; Ror1Chronic lymphocytic leukemia (CLL) originates from B lymphocytes, which differ in activation and maturation stage and are derived from antigen experienced B cells with different immunoglobulin heavy chain variable (IgVH) gene mutations. 1 Patients with mutated IgVH genes have a better prognosis compared to patients with unmutated genes. 2,3 Global gene expression profiling studies have revealed partly distinguishing but in general overlapping expression profiles in mutated and unmutated leukemic B cells, suggesting a common phenotype. 4,5 Gene expression profiling studies showed a 43.8-fold increase of the orphan receptor tyrosine kinase (RTK) ROR1 in CLL cells. 4 Ror1 is a member of the RTK family of orphan receptors related to muscle specific kinase and Trk neurotrophin receptors. [6][7][8] Ror receptors are cell surface receptors participating in signal transduction, cell-cell interaction, regulation of cell proliferation, differentiation, cell metabolism and survival. 7,9 They are evolutionarily highly conserved between different species e.g., human, mouse, Drosophila and C. elegans, suggesting important biological functions.The human ROR1 gene has a coding region of 2814 bp with a predicted 937 amino acids sequence and 105 kDa protein size including an Ig-like domain, cysteine-rich domain, kringle domain, tyrosine kinase domain and p...

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“…32 Furthermore, CLL cells have been found to be efficient APC, presenting, in CLL cells, the highly upregulated protein fibromodulin in HLA-A2. 50,51 Pre-activation in vitro also enabled the expanded, fibromodulinspecific T cells to secrete IFNg upon recognition of the antigen. 51 This CD5 + B-cell-specific antigen-presentation thus enabled the expansion of autologous tumor-specific T cells.…”

confidence: 99%

Myelin protein zero is naturally processed in the B cells of monoclonal gammopathy of undetermined significance of immunoglobulin M isotype: aberrant triggering of a patient's T cells

Hellqvist

Kvarnström²,

Söderberg³

et al. 2009

Haematologica

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BackgroundMonoclonal gammopathy of undetermined significance of immunoglobulin M isotype is a condition with clonally expanded B cells, recently suggested to have an infectious origin. This monoclonal gammopathy is frequently associated with polyneuropathy and antibodies against myelin protein zero, whereas the role of the T cells remains largely unknown. We analyzed protein zero-specific B cells, as antigen-presenting cells, and their capacity to activate T helper cells. Design and MethodsWe used a well-characterized monoclonal gammopathy of undetermined significance-derived B-cell line, TJ2, expressing anti-protein zero immunoglobulin M. The ability of TJ2 cells to bind, endocytose, process, and present protein zero was investigated by receptor-clustering and immunofluorescence. The activation of protein zero-specific autologous T cells was studied by measuring interleukin-2 and interferon-g with flow cytometry, immunobeads, and enzymelinked immunospot assays. ResultsSurface-receptor clustering and endocytosis of receptor-ligand (immunoglobulin M/protein zero) complexes were pronounced after exposure to protein zero. Naturally processed or synthetic protein zero peptide (194-208)-pulsed TJ2 cells significantly induced interleukin-2 secretion from autologous T cells compared to control antigen-pulsed cells (P<0.001). The numbers of interferon-g-producing T helper cells, including CD4 + /CD8 + cells, were also significantly increased (P=0.0152). Affinity-isolated naturally processed myelin peptides were potent interferon-g stimulators for autologous peripheral blood mononuclear cells, but not for control peripheral blood mononuclear cells. ConclusionsWe show for the first time that myelin protein zero is naturally processed in B cells from monoclonal gammopathy of undetermined significance of immunoglobulin M isotype, acting as aberrant antigen-presenting cells in activation of a patient's T helper cells. Our findings cast new light on the important role of autoreactive protein zero-specific B cells in the induction of the pathogenic T-cell responses found in nerve lesions of patients with monoclonal gammopathy of undetermined significance with peripheral neuropathy. 's T cells. Haematologica. 2010;95:627-636. doi:10.3324/haematol.2009 This is an open-access paper. © F e r r a t a S t o r t i F o u n d a t i o n

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Fibromodulin, an extracellular matrix protein: characterization of its unique gene and protein expression in B-cell chronic lymphocytic leukemia and mantle cell lymphoma

Abstract: Fibromodulin is an extracellular matrix protein normally produced by collagen-rich tissues; the fibromodulin gene has been found to be the most overexpressed gene in B-cell chronic lymphocytic leukemia. In this study, fibromodulin was expressed at the gene level (

Cited by 56 publications

References 56 publications

Gene expression profiling of B lymphocytes and plasma cells from Waldenström's macroglobulinemia: comparison with expression patterns of the same cell counterparts from chronic lymphocytic leukemia, multiple myeloma and normal individuals

Gene expression profiling of B lymphocytes and plasma cells from Waldenström's macroglobulinemia: comparison with expression patterns of the same cell counterparts from chronic lymphocytic leukemia, multiple myeloma and normal individuals

Ror1, a cell surface receptor tyrosine kinase is expressed in chronic lymphocytic leukemia and may serve as a putative target for therapy

Myelin protein zero is naturally processed in the B cells of monoclonal gammopathy of undetermined significance of immunoglobulin M isotype: aberrant triggering of a patient's T cells

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