title: Mantle cell lymphomas with low levels of cyclin D1 long mRNA transcripts are highly proliferative and can be discriminated by elevated cyclin A2 and cyclin B1.
abstract: The role of transcript variants of cyclin D1 in cancer biology is unclear. Most tumors with high levels of cyclin D1 express 2 transcripts due to alternative splicing: one full-length transcript of 4.4 kb and one short transcript of approximately 1.7 kb. The short transcript lacks part of the 3'UTR region regulating mRNA stability and has a longer half-life. In our study, the contribution of each of these mRNAs to gene expression and cell proliferation has been investigated in mantle cell lymphoma (MCL), a B cell lymphoma characterized by a specific gene translocation resulting in enhanced expression of cyclin D1. A subset of MCL tumors with low levels of the long cyclin D1 transcript (cyclin D1 3'UTR) was identified by quantitative PCR and by oligonucleotide array hybridization. This tumor-subset had 3.4-fold higher levels of the short form of cyclin D1 mRNA (p < 0.0001) and had higher expression of cyclin D1 protein. Gene expression analysis identified a number of cell-cycle regulatory genes as upregulated. There was a significant difference in frequencies of cyclin B1 (p = 0.0006) and cyclin A2 (p = 0.0006) positive cells that discriminated MCL with low cyclin D1 3'UTR from other highly proliferative MCL. Among differentially expressed genes, there was a highly upregulated gene with homology to the group of cell-cycle promoting E2F transcription partners, E2F_TDP5. Several of the upregulated genes, such as TOP2A, AURORA A and RRM2 may influence a response to therapy. Identification of MCL with low cyclin D1 3'UTR is important because it seems to be associated with shorter overall survival.
authors.affiliation: Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet and Karolinska University Hospital,Stockholm, Sweden. birgitta.sander@labmed.ki.se
authors.forename: Birgitta
authors.initials: B
authors.lastname: Sander
authors.forename: Jenny
authors.initials: J
authors.lastname: Flygare
authors.forename: Anna
authors.initials: A
authors.lastname: Porwit-Macdonald
authors.forename: C I Edvard
authors.initials: CI
authors.lastname: Smith
authors.forename: Emma
authors.initials: E
authors.lastname: Emanuelsson
authors.forename: Eva
authors.initials: E
authors.lastname: Kimby
authors.forename: Johan
authors.initials: J
authors.lastname: Liden
authors.forename: Birger
authors.initials: B
authors.lastname: Christensson
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing; D002455:Cell Division; D019938:Cyclin D1 / Q000235:genetics*; D017931:DNA Primers; D005260:Female; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
chemical_list: D020413:3' Untranslated Regions; D017931:DNA Primers; D012333:RNA, Messenger; D019938:Cyclin D1