Radiation leukemia virus common integration at the Kis2 locus: simultaneous overexpression of a novel noncoding RNA and of the proximal Phf6 gene.
Retroviral tagging has been used extensively and successfully to identify genes implicated in cancer pathways. In order to find oncogenes implicated in T-cell leukemia, we used the highly leukemogenic radiation leukemia retrovirus VL3 (RadLV/VL3). We applied the inverted PCR technique to isolate and analyze sequences flanking proviral integrations in RadLV/VL3-induced T lymphomas. We found retroviral integrations in c-myc and Pim1 as already reported but we also identified for the first time Notch1 as a RadLV common integration site. More interestingly, we found a new RadLV common integration site that is situated on mouse chromosome X (XA4 region, bp 45091000). This site has also been reported as an SL3-3 and Moloney murine leukemia virus integration site, which strengthens its implication in murine leukemia virus-induced T lymphomas. This locus, named Kis2 (Kaplan Integration Site 2), was found rearranged in 11% of the tumors analyzed. In this article, we report not only the alteration of the Kis2 gene located nearby in response to RadLV integration but also the induction of the expression of Phf6, situated about 250 kbp from the integration site. The Kis2 gene encodes five different alternatively spliced noncoding RNAs and the Phf6 gene codes for a 365-amino-acid protein which contains two plant homology domain fingers, recently implicated in the Börjeson-Forssman-Lehmann syndrome in humans. With the recent release of the mouse genome sequence, high-throughput retroviral tagging emerges as a powerful tool in the quest for oncogenes. It also allows the analysis of large DNA regions surrounding the integration locus.
Landais
Séverine
S
Département des Sciences Biologiques, Université du Québec à Montréal, Canada.
Quantin
Renaud
R
Rassart
Eric
E
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000378:metabolism*; D007942:Leukemia, Experimental / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D022661:RNA, Untranslated / Q000378:metabolism*; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism*; D016721:Radiation Leukemia Virus / Q000502:physiology*; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface / Q000235:genetics; D012192:Retroviridae Infections / Q000821:virology; D016415:Sequence Alignment; D014157:Transcription Factors / Q000235:genetics; D014412:Tumor Virus Infections / Q000821:virology; D016662:Virus Integration; D014960:X Chromosome / Q000235:genetics; D056427:t-Complex Genome Region
D004268:DNA-Binding Proteins; D008869:Microtubule-Associated Proteins; C497762:Notch1 protein, mouse; D009687:Nuclear Proteins; D012333:RNA, Messenger; D022661:RNA, Untranslated; D012367:RNA, Viral; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D014157:Transcription Factors