No impact of lentiviral transduction on hematopoietic stem/progenitor cell telomere length or gene expression in the rhesus macaque model

Mol Ther. 2014 Jan;22(1):52-8. doi: 10.1038/mt.2013.168. Epub 2013 Jul 18.

Abstract

The occurrence of clonal perturbations and leukemia in patients transplanted with gamma-retroviral (RV) vector-transduced autologous hematopoietic stem and progenitor cells (HSPCs) has stimulated extensive investigation, demonstrating that proviral insertions may perturb adjacent proto-oncogene expression. Although enhancer-deleted lentiviruses are less likely to result in insertional oncogenesis, there is evidence that they may perturb transcript splicing, and one patient with a benign clonal expansion of lentivirally transduced HPSC has been reported. The rhesus macaque model provides an opportunity for informative long-term analysis to ask whether transduction impacts on long-term HSPC properties. We used two techniques to examine whether lentivirally transduced HSPCs from eight rhesus macaques transplanted 1-13.5 years previously are perturbed at a population level, comparing telomere length as a measure of replicative history and gene expression profile of vector positive versus vector negative cells. There were no differences in telomere lengths between sorted GFP+ and GFP- blood cells, suggesting that lentiviral (LV) transduction did not globally disrupt replicative patterns. Bone marrow GFP+ and GF- CD34+ cells showed no differences in gene expression using unsupervised and principal component analysis. These studies did not uncover any global long-term perturbation of proliferation, differentiation, or other important functional parameters of transduced HSPCs in the rhesus macaque model.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Antigens, CD34 / metabolism
  • Gene Expression*
  • Genetic Vectors / genetics*
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Hematopoietic Stem Cell Transplantation*
  • Hematopoietic Stem Cells / metabolism*
  • Lentivirus / genetics*
  • Leukocytes, Mononuclear / metabolism
  • Macaca mulatta
  • Telomere*
  • Transcriptome
  • Transduction, Genetic*
  • Transgenes

Substances

  • Antigens, CD34
  • Green Fluorescent Proteins