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

Authors: Stephanie E SE. Sellers, Bogdan B. Dumitriu, Mary J MJ. Morgan, William M WM. Hughes, Colin O CO. Wu, Nalini N. Raghavarchari, Yanqin Y. Yang, Naoya N. Uchida, John F JF. Tisdale, Dong S DS. An, Irvin S IS. Chen, Peiman P. Hematti, Robert E RE. Donahue, Andre A. Larochelle, Neal S NS. Young, Rodrigo T RT. Calado, Cynthia E CE. Dunbar
Published: 07/18/2013, Molecular therapy : the journal of the American Society of Gene Therapy


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.

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