Clonal dominance of hematopoietic stem cells triggered by retroviral gene marking.
Gene marking with replication-defective retroviral vectors has been used for more than 20 years to track the in vivo fate of cell clones. We demonstrate that retroviral integrations themselves may trigger nonmalignant clonal expansion in murine long-term hematopoiesis. All 29 insertions recovered from clones dominating in serially transplanted recipients affected loci with an established or potential role in the self-renewal or survival of hematopoietic stem cells. Transcriptional dysregulation occurred in all 12 insertion sites analyzed. These findings have major implications for diagnostic gene marking and the discovery of genes regulating stem cell turnover.
Kustikova
Olga
O
Bone Marrow Transplantation, University Hospital Eppendorf, Martinistrasse 52, 20251 Hamburg, Germany.
Fehse
Boris
B
Modlich
Ute
U
Yang
Min
M
Düllmann
Jochen
J
Kamino
Kenji
K
von Neuhoff
Nils
N
Schlegelberger
Brigitte
B
Li
Zhixiong
Z
Baum
Christopher
C
D000818:Animals; D018952:Antigens, CD34 / Q000235:genetics; D016026:Bone Marrow Transplantation; D004268:DNA-Binding Proteins / Q000235:genetics; D015536:Down-Regulation; D005822:Genetic Vectors; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D022521:Ligase Chain Reaction; D000074008:MDS1 and EVI1 Complex Locus Protein; D051379:Mice; D008810:Mice, Inbred C57BL; D016254:Mutagenesis, Insertional; D016133:Polymerase Chain Reaction; D011519:Proto-Oncogenes / Q000235:genetics; D012190:Retroviridae / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic; D019076:Transgenes; D015854:Up-Regulation; D016662:Virus Integration
D018952:Antigens, CD34; D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; C499305:Mecom protein, mouse; D014157:Transcription Factors