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ABSTRACT: The mutation status of genes involved in the NF-κB signaling pathway in splenic marginal zone lymphoma was examined. DNA sequence analysis of four genes was performed: CD79A, CD79B, CARD11, and MYD88 that are activated through BCR signaling or Toll-like and interleukin signaling. A single point mutation was detected in the CD79B gene (Y196H) in one of ten SMZL cases. Additionally, one point mutation was identified in the MYD88 gene (L265P) in another SMZL case. No mutations were revealed in CD79A or CARD11 genes in these SMZL cases. Neither were mutations detected in these four genes studied in 13 control MZL samples. Interestingly, the two cases with mutations of CD79B and MYD88 showed increased numbers of immunoblasts spread among the smaller and typical marginal zone lymphoma cells. Although SMZL shows few mutations of NF-κB signaling genes, our results indicate that the presence of these mutations is associated with a higher histological grade.
ISRN oncology. 01/2013; 2013:252318.
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Abdirashid A Warsame,
Hans-Christian Aasheim,
Kjell Nustad, Gunhild Trøen,
Anne Tierens,
Vivian Wang,
Ulla Randen,
Hiep P Dong,
Sverre Heim,
Andreas Brech,
Jan Delabie
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ABSTRACT: One-third of all splenic marginal zone lymphomas (SMZL) use the IgH VH1-02 gene. These cases are usually not associated with hepatitis C virus infection. Of interest, the rearranged VH1-02 genes display similar complementarity determining regions 3, a finding confirmed by our study. The latter suggests that these SMZL may produce antibodies with similar reactivity. We produced recombinant antibodies from 5 SMZL cases with VH1-02 gene rearrangement to study the binding reactivity of these antibodies. Surprisingly, the recombinant antibodies demonstrated poly- and self-reactivity as demonstrated by their reactivity with nuclear, cytoplasmic, as well as membranous antigens expressed by human cells and by reactivity with human serum. This polyreactivity was specific as demonstrated by ELISA. The antibodies did not react with proteins on the cell surface that are induced by apoptosis as shown for antibodies produced by chronic lymphatic leukemia with VH1-02 gene rearrangement. The results indicate that a common subset of SMZL arises from polyreactive B cells, a subset of marginal zone B cells that are important in the immunologic defense against infection.
Blood 07/2011; 118(12):3331-9. · 9.90 Impact Factor
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ABSTRACT: We report the clinical, cytogenetic, and molecular data of two patients diagnosed with acute lymphoblastic leukemia characterized by the rare translocation t(12;17)(p13;q12). This translocation has been reported in 25 cases and its putative molecular consequence, the formation of a TAF15-ZNF384 fusion gene, in only six cases. We used fluorescence in situ hybridization followed by long-range polymerase chain reaction to find the translocation breakpoints. A fusion between TAF15 and ZNF384 was identified and confirmed by nucleotide sequencing. Our results confirm that the t(12;17)(p13;q12) leading to a TAF15-ZNF384 fusion gene characterizes a specific subgroup of acute lymphoblastic leukemia and suggest that two different breakpoints in TAF15 may be involved. Whether the two variants of the TAF15-ZNF384 fusion that these correspond to are in any way hematologically or prognostically different, is unknown.
Cancer Genetics 03/2011; 204(3):147-52.
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Marianne Brodtkorb Eide,
Knut Liestøl,
Ole Christian Lingjaerde,
Marit E Hystad,
Stine H Kresse,
Leonardo Meza-Zepeda,
Ola Myklebost, Gunhild Trøen,
Hege Vangstein Aamot,
Harald Holte,
Erlend Bremertun Smeland,
Jan Delabie
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ABSTRACT: Our aim was to examine the genetics of clonal evolution in follicular lymphoma (FL) and to identify genetic alterations associated with disease progression. A total of 100 biopsies from 44 patients diagnosed with t(14;18)-positive FL were examined by array comparative genomic hybridization. In 20 patients the patterns of somatic hypermutations (SHMs) in the variable region of heavy chain gene were additionally analyzed. Gain of chromosome X in male samples was a marker for poor outcome (P < .01). Gains involving chromosome 2, 3q, and 5 were exclusively present in FL biopsies from cases with higher grade transformation and were among the copy number alterations (CNAs) associated with inferior survival. Although we noted a trend for increasing genomic complexity in initial versus late FL samples, the overall frequencies of CNAs in initial and late FL biopsies showed a surprisingly stable pattern through the course of the disease. In 27 of cases the initial samples harbored CNAs that were absent in relapse samples, indicating that tumor cell clones at relapse were not direct descendants of initially dominating clones. The pattern of SHMs confirmed parallel development of tumor cell clones in 14 cases. Our findings support the hypothesis of common progenitor cells in FL.
Blood 09/2010; 116(9):1489-97. · 9.90 Impact Factor
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ABSTRACT: Malignant lymphomas comprise a heterogeneous group of non-solid tumors originating in lymphocytes at different maturation stages. The diagnosis is based on a traditional histopathological diagnostic procedure supplemented with immunophenotyping, cytogenetics, molecular genetic analyses and clinical information. This article describes experimental molecular diagnostics, mainly based on microarray-based gene expression technology.
Results achieved through an international multicentre project (headed by the National Cancer Institute in the USA), in which the Norwegian Radium Hospital has taken part as the only Nordic institution, are summarized. The findings are discussed in light of other relevant studies identified through a non-systematic search in PubMed.
New clinically relevant subgroups of malignant B-cell lymphomas have been characterized. Retrospective survival analyses have shown correlations between gene expression profiles and patient outcome and have provided important biological knowledge, which has led to new targeted treatments (currently being tested in clinical studies).
As a supplement to today's diagnostics, molecular diagnostics yields an improved diagnostic precision and opens up for new treatment possibilities for patients with malignant lymphomas.
Tidsskrift for den Norske laegeforening 11/2009; 129(22):2352-6.
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ABSTRACT: Transdifferentiation of B cell lymphoma of germinal center cell origin to histiocytic sarcoma has recently been described but is a rare occurrence. The cause for loss of B cell differentiation in these lymphomas is unknown. We investigated whether somatic hypermutation of the PAX-5 gene, a transcription factor that is important for maintaining B cell identity and is frequently mutated in B cell lymphomas of germinal center cell origin, might be a cause for loss of PAX-5 expression and thus B cell phenotype. However, no somatic hypermutation of the PAX-5 gene was detected in the two cases we studied. The molecular basis for transdifferentiation of B cell lymphoma to histiocytic sarcoma remains therefore unresolved.
Journal of Hematopathology 06/2009; 2(3):135-41.
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Haematologica 08/2008; 93(7):1107-9. · 6.42 Impact Factor
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Gunhild Trøen,
Vigdis Nygaard,
Tor-Kristian Jenssen,
Ida Münster Ikonomou,
Anne Tierens,
Estella Matutes,
Alicja Gruszka-Westwood,
Daniel Catovsky,
Ola Myklebost,
Grete Lauritzsen,
Eivind Hovig,
Jan Delabie
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ABSTRACT: Splenic marginal zone lymphoma (SMZL) is a lymphoma type of putative marginal zone B-cell origin. No specific genetic alterations have yet been demonstrated in SMZL. Clinically, SMZL is a low-grade B-cell non-Hodgkin lymphoma. However, the presence of p53 mutation, 7q22-7q32 deletion or the absence of somatic hypermutations of immunoglobulin genes has been correlated with a worse prognosis. In this study, we analyzed genome-wide gene expression of 24 cases of SMZL using the microarray technique. The AP-1 transcription factors c-jun, junD, junB, and c-fos as well as Notch2 were found to be specifically up-regulated. These data were confirmed by real-time PCR and immunohistochemical staining of tissue sections. The absence of concordant high expression of the MAP kinases, the signaling cascade leading to AP-1 up-regulation, suggests autoregulation of the AP-1 transcription factors and an important role in SMZL oncogenesis. High expression of Notch2, a transcription factor that induces marginal zone B-cell differentiation, is highly suggestive for a marginal zone B-cell origin of SMZL. In addition, SMZL with the 7q deletion showed high expression of TGF-beta1 and low expression of the DNA helicase XPB, a crucial part of the nucleotide excision repair complex, possibly explaining the more aggressive clinical course of those cases.
Journal of Molecular Diagnostics 12/2004; 6(4):297-307. · 3.58 Impact Factor
