Retroviral vector insertion sites associated with dominant hematopoietic clones mark "stemness" pathways.
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Retroviral vector insertion sites associated with dominant hematopoietic clones mark "stemness" pathways. / Kustikova, Olga S; Geiger, Hartmut; Li, Zhixiong; Brugman, Martijn H; Chambers, Stuart M; Shaw, Chad A; Pike-Overzet, Karin; de Ridder, Dick; Staal, Frank J T; von Keudell, Gottfried; Cornils, Kerstin; Nattamai, Kalpana Jekumar; Modlich, Ute; Wagemaker, Gerard; Goodell, Margaret A; Fehse, Boris; Baum, Christopher.
in: BLOOD, Jahrgang 109, Nr. 5, 5, 2007, S. 1897-1907.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Retroviral vector insertion sites associated with dominant hematopoietic clones mark "stemness" pathways.
AU - Kustikova, Olga S
AU - Geiger, Hartmut
AU - Li, Zhixiong
AU - Brugman, Martijn H
AU - Chambers, Stuart M
AU - Shaw, Chad A
AU - Pike-Overzet, Karin
AU - de Ridder, Dick
AU - Staal, Frank J T
AU - von Keudell, Gottfried
AU - Cornils, Kerstin
AU - Nattamai, Kalpana Jekumar
AU - Modlich, Ute
AU - Wagemaker, Gerard
AU - Goodell, Margaret A
AU - Fehse, Boris
AU - Baum, Christopher
PY - 2007
Y1 - 2007
N2 - 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.
AB - 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.
M3 - SCORING: Zeitschriftenaufsatz
VL - 109
SP - 1897
EP - 1907
JO - BLOOD
JF - BLOOD
SN - 0006-4971
IS - 5
M1 - 5
ER -