title: Murine leukemia retrovirus integration induces the formation of transcription factor complexes on palindromic sequences in the signal transducer and activator of transcription factor 5a gene during the development of pre-B lymphomagenesis.
abstract: Murine leukemia retrovirus (MLV) vectors are highly effective tools for introducing a foreign gene into a target host genome. However, it remains unclear how integrated retroviral promoter activity is influenced by the upstream or downstream sequences and how the host cell phenotype is influenced by the integrated promoter activity. Herein, we analyzed a set of pre-B lymphoma clones in which the MLV genome was integrated into the signal transducer and activator of transcription factor 5a (Stat5a) gene. Among the clones, the lymphoma clones with a provirus integrating into the middle position of the palindromic target sequences showed significantly higher transcription of the Stat5a gene; and p300 and other transcriptional factors formed complexes, with binding to the proviral-host junctional DNA segment. By using a luciferase assay, the upstream and downstream sequences of the provirus contributed to the up-regulation of proviral promoter activity. In concomitance with the higher Stat5a transcription, the immunoglobulin gene recombination was arrested. Antiapoptotic activity was significantly higher, with an increase in Bcl-xL, one of the targets of STAT5A, when IL-7 was supplied. Thus, a minute difference between MLV integration sites can lead to large differences in the host phenotype through the formation of transcription factor complexes on the proviral-host junctional DNA segment, suggesting that caution is necessary in monitoring integration sites when working with MLV vectors.
authors.affiliation: Department of Forensic Medicine and Molecular Pathology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. tsuruyam@fp.med-u.ac.jp
authors.forename: Tatsuaki
authors.initials: T
authors.lastname: Tsuruyama
authors.forename: Takuya
authors.initials: T
authors.lastname: Hiratsuka
authors.forename: Guang
authors.initials: G
authors.lastname: Jin
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Imai
authors.forename: Haruya
authors.initials: H
authors.lastname: Takeuchi
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Maruyama
authors.forename: Kazuya
authors.initials: K
authors.lastname: Kanaya
authors.forename: Munetaka
authors.initials: M
authors.lastname: Ozeki
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Takakuwa
authors.forename: Hironori
authors.initials: H
authors.lastname: Haga
authors.forename: Keiji
authors.initials: K
authors.lastname: Tamaki
authors.forename: Takuro
authors.initials: T
authors.lastname: Nakamura
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D002454:Cell Differentiation; D002999:Clone Cells; D050989:GATA2 Transcription Factor / Q000378:metabolism; D017930:Genes, Reporter / Q000235:genetics; D007147:Immunoglobulin Light Chains / Q000235:genetics; D055029:Inverted Repeat Sequences / Q000235:genetics*; D009052:Leukemia Virus, Murine / Q000235:genetics*; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D011230:Precancerous Conditions / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011533:Proviruses / Q000235:genetics; D020395:Receptors, Interleukin-7 / Q000378:metabolism; D011995:Recombination, Genetic / Q000235:genetics; D050799:STAT5 Transcription Factor / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism*; D016662:Virus Integration / Q000235:genetics*
chemical_list: D050989:GATA2 Transcription Factor; D007147:Immunoglobulin Light Chains; D020395:Receptors, Interleukin-7; D050799:STAT5 Transcription Factor; C494093:Stat5a protein, mouse; D014157:Transcription Factors