Retroviral vector insertion sites associated with dominant hematopoietic clones mark "stemness" pathways

Blood. 2007 Mar 1;109(5):1897-907. doi: 10.1182/blood-2006-08-044156. Epub 2006 Nov 21.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Transplantation
  • Cell Differentiation*
  • Cell Line, Tumor
  • Databases, Factual
  • Genetic Vectors / genetics*
  • Hematopoiesis*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mutation / genetics
  • Polymerase Chain Reaction
  • Probability
  • Retroviridae / genetics*
  • Stem Cells / cytology*
  • Stem Cells / metabolism*
  • Transcription, Genetic / genetics