The Ig heavy chain 3' end confers a posttranscriptional processing advantage to Bcl-2-IgH fusion RNA in t(14;18) lymphoma.
The chromosomal translocation t(14;18) in lymphoma leads to an overproduction of the Bcl-2 protein on the basis of increased Bcl-2 mRNA levels. Whereas the juxtaposition of Bcl-2 with the Ig heavy chain locus causes a transcriptional activation, 70% of the lymphomas also produce Bcl-2-Ig fusion RNAs with Ig 3' ends. Using S1 nuclease protection assays that can discriminate between nuclear RNA precursors and spliced mRNA, we found that the fusion RNAs in t(14;18) cell lines exhibit an additional posttranscriptional processing advantage. Transfection experiments with artificial genes containing various Bcl-2 or Ig 3' ends show that this effect is (1) related to RNA splicing and/or nucleocytoplasmic transport; (2) independent of transcriptional activation by the heavy chain enhancer; (3) dependent on the presence of the JH-CH and C-gamma1 Ig introns; and (4) tissue specific for B cells. This constitutes a novel mechanism of oncogene deregulation unrelated to transcriptional activation or half-life prolongation. The data further support the existence of a tissue-specific posttranscriptional pathway of Ig regulation in B cells.
Petrovic
A S
AS
Department of Medicine I, Division of Hematology, University of Vienna Medical School, Vienna, Austria.
Young
R L
RL
Hilgarth
B
B
Ambros
P
P
Korsmeyer
S J
SJ
Jaeger
U
U
D000199:Actins / Q000235:genetics; D000818:Animals; D001692:Biological Transport; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics* / Q000648:ultrastructure; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics* / Q000648:ultrastructure; D004742:Enhancer Elements, Genetic; D015972:Gene Expression Regulation, Neoplastic; D005803:Genes, Immunoglobulin; D019254:Genes, bcl-2; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D008224:Lymphoma, Follicular / Q000235:genetics*; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics*; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000378:metabolism*; D014162:Transfection; D014178:Translocation, Genetic / Q000235:genetics*; D014407:Tumor Cells, Cultured
D000199:Actins; D007143:Immunoglobulin Heavy Chains; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D012334:RNA, Neoplasm