Transcriptomics

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Gene expression analysis of lentivirally-transduced rhesus macaque CD34+ cells long-term following transplant


ABSTRACT: The occurrence of clonal perturbations and leukemia in patients transplanted with retrovirally-transduced autologous hematopoietic stem and progenitor cells (HSPCs) has stimulated extensive investigation, demonstrating that proviral insertions 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 utilized 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 transduction did not globally disrupt replicative patterns. Bone marrow GFP+ and GFP- 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. CD34+ hematopoietic stem and progenitor cells were purified from bone marrow aspirates obtained from 4 rhesus macaques 3-9 years following transplantation with lentivirally-transduced autologous hematopoietic stem and progenitor cells. All lentiviral vectors contained the GFP marker gene. The CD34+ cells from each animal were sorted via flow cytometry into GFP+ and GFP- fractions, and RNA from these cells was used for Affymetrix gene expression analysis as detailed below. There were two samples, GFP+ and GFP-, from each of 4 animals.

ORGANISM(S): Macaca mulatta  

SUBMITTER: Stephanie Sellers   Cynthia E Dunbar  Yanqin Yang 

PROVIDER: E-GEOD-46032 | ArrayExpress | 2013-11-05

SECONDARY ACCESSION(S): GSE46032PRJNA196934

REPOSITORIES: GEO, ArrayExpress

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Publications

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

Sellers Stephanie E SE   Dumitriu Bogdan B   Morgan Mary J MJ   Hughes William M WM   Wu Colin O CO   Raghavarchari Nalini N   Yang Yanqin Y   Uchida Naoya N   Tisdale John F JF   An Dong S DS   Chen Irvin S IS   Hematti Peiman P   Donahue Robert E RE   Larochelle Andre A   Young Neal S NS   Calado Rodrigo T RT   Dunbar Cynthia E CE  

Molecular therapy : the journal of the American Society of Gene Therapy 20130718 1


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 e  ...[more]

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