A bcl-2/IgH antisense transcript deregulates bcl-2 gene expression in human follicular lymphoma t(14;18) cell lines.
The 14;18 chromosome translocation, characteristic of most human follicular B-cell lymphomas, juxtaposes the bcl-2 gene with the IgH locus, creating a bcl-2/IgH hybrid gene. By mechanisms that are still under investigation, this event increases the cellular levels of the bcl-2 mRNA and thereby induces an overproduction of the antiapoptotic BCL-2 protein which is likely responsible for neoplastic transformation. In an effort to identify potential upregulators of bcl-2 activity in t(14;18) cells, we found, by strand-specific RT-PCR, a bcl-2 antisense transcript that is present in the t(14;18) DOHH2 and SU-DHL-4 but not in the t(14;18)-negative Raji and Jurkat lymphoid cell lines, and thus appears to be dependent on the bcl-2/IgH fusion. This antisense transcript is a hybrid bc1-2/IgH RNA, that originates in the IgH locus, encompasses the t(14;18) fusion site and spans at least the complete 3' UTR region of the bcl-2 mRNA. To achieve some insight into its biological function, we treated the t(14;18) DOHH2 cell line with oligonucleotides (ODNs) by specifically targeting the bc1-2/IgH antisense strand. These ODNs lowered bcl-2 gene expression, inhibited neoplastic cell growth by inducing apoptosis. We would like to propose the hypothesis that the bc1-2/IgH antisense transcript may contribute, by an unknown mechanism, to upregulation of bcl-2 gene expression in t(14;18) cells. The possibility has been considered that the hybrid antisense transcript mask AU-rich motifs present in the 3' UTR of the bcl-2 mRNA characterized in other genes as mRNA destabilizing elements.
Capaccioli
S
S
Institute of General Pathology, University of Florence, Italy.
Quattrone
A
A
Schiavone
N
N
Calastretti
A
A
Copreni
E
E
Bevilacqua
A
A
Canti
G
G
Gong
L
L
Morelli
S
S
Nicolin
A
A
D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D002051:Burkitt Lymphoma / Q000235:genetics / Q000473:pathology; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics*; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics*; D004742:Enhancer Elements, Genetic; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D005803:Genes, Immunoglobulin; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000473:pathology; D008224:Lymphoma, Follicular / Q000235:genetics*; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2; D016372:RNA, Antisense / Q000235:genetics*; D014158:Transcription, Genetic; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured
D007143:Immunoglobulin Heavy Chains; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016372:RNA, Antisense