Retroviral vector insertion sites associated with dominant hematopoietic clones mark "stemness" pathways.
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.
Kustikova
Olga S
OS
Department of Experimental Hematology, Hannover Medical School, Germany.
Geiger
Hartmut
H
Li
Zhixiong
Z
Brugman
Martijn H
MH
Chambers
Stuart M
SM
Shaw
Chad A
CA
Pike-Overzet
Karin
K
de Ridder
Dick
D
Staal
Frank J T
FJ
von Keudell
Gottfried
G
Cornils
Kerstin
K
Nattamai
Kalpana Jekumar
KJ
Modlich
Ute
U
Wagemaker
Gerard
G
Goodell
Margaret A
MA
Fehse
Boris
B
Baum
Christopher
C
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