title: Retroviral vector insertion sites associated with dominant hematopoietic clones mark "stemness" pathways.
abstract: Evidence from model organisms and clinical trials reveals that the random insertion of retrovirus-based vectors in the genome of long-term repopulating hematopoietic cells may increase self-renewal or initiate malignant transformation. Clonal dominance of nonmalignant cells is a particularly interesting phenotype as it may be caused by the dysregulation of genes that affect self-renewal and competitive fitness. We have accumulated 280 retrovirus vector insertion sites (RVISs) from murine long-term studies resulting in benign or malignant clonal dominance. RVISs (22.5%) are located in or near (up to 100 kb [kilobase]) to known proto-oncogenes, 49.6% in signaling genes, and 27.9% in other or unknown genes. The resulting insertional dominance database (IDDb) shows substantial overlaps with the transcriptome of hematopoietic stem/progenitor cells and the retrovirus-tagged cancer gene database (RTCGD). RVISs preferentially marked genes with high expression in hematopoietic stem/progenitor cells, and Gene Ontology revealed an overrepresentation of genes associated with cell-cycle control, apoptosis signaling, and transcriptional regulation, including major "stemness" pathways. The IDDb forms a powerful resource for the identification of genes that stimulate or transform hematopoietic stem/progenitor cells and is an important reference for vector biosafety studies in human gene therapy.
authors.affiliation: Department of Experimental Hematology, Hannover Medical School, Germany.
authors.forename: Olga S
authors.initials: OS
authors.lastname: Kustikova
authors.forename: Hartmut
authors.initials: H
authors.lastname: Geiger
authors.forename: Zhixiong
authors.initials: Z
authors.lastname: Li
authors.forename: Martijn H
authors.initials: MH
authors.lastname: Brugman
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Chambers
authors.forename: Chad A
authors.initials: CA
authors.lastname: Shaw
authors.forename: Karin
authors.initials: K
authors.lastname: Pike-Overzet
authors.forename: Dick
authors.initials: D
authors.lastname: de Ridder
authors.forename: Frank J T
authors.initials: FJ
authors.lastname: Staal
authors.forename: Gottfried
authors.initials: G
authors.lastname: von Keudell
authors.forename: Kerstin
authors.initials: K
authors.lastname: Cornils
authors.forename: Kalpana Jekumar
authors.initials: KJ
authors.lastname: Nattamai
authors.forename: Ute
authors.initials: U
authors.lastname: Modlich
authors.forename: Gerard
authors.initials: G
authors.lastname: Wagemaker
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Goodell
authors.forename: Boris
authors.initials: B
authors.lastname: Fehse
authors.forename: Christopher
authors.initials: C
authors.lastname: Baum
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D016208:Databases, Factual; D005822:Genetic Vectors / Q000235:genetics*; D006410:Hematopoiesis; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D016133:Polymerase Chain Reaction; D011336:Probability; D012190:Retroviridae / Q000235:genetics*; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics