Constitutive expression of the AP-1 transcription factors c-jun, junD, junB, and c-fos and the marginal zone B-cell transcription factor Notch2 in splenic marginal zone lymphoma.
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.
Trøen
Gunhild
G
Department of Pathology, The Norwegian Radium Hospital, University of Oslo, Montebello N-0310, Oslo, Norway. gunhild.troen@labmed.uio.no.
Nygaard
Vigdis
V
Jenssen
Tor-Kristian
TK
Ikonomou
Ida Münster
IM
Tierens
Anne
A
Matutes
Estella
E
Gruszka-Westwood
Alicja
A
Catovsky
Daniel
D
Myklebost
Ola
O
Lauritzsen
Grete
G
Hovig
Eivind
E
Delabie
Jan
J
D000483:Alleles; D002897:Chromosomes, Human, Pair 7; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation; D005456:Fluorescent Dyes / Q000494:pharmacology; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D016758:Genes, jun / Q000235:genetics*; D016158:Genes, p53; D006801:Humans; D007150:Immunohistochemistry; D016393:Lymphoma, B-Cell / Q000378:metabolism*; D018895:Microsatellite Repeats; D009154:Mutation; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D011379:Prognosis; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis*; D051883:Receptor, Notch2; D011956:Receptors, Cell Surface / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018808:Transcription Factor AP-1 / Q000096:biosynthesis*; D014158:Transcription, Genetic; D015854:Up-Regulation
D005456:Fluorescent Dyes; C497764:NOTCH2 protein, human; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D051883:Receptor, Notch2; D011956:Receptors, Cell Surface; D018808:Transcription Factor AP-1; D004247:DNA