Retroviral vector integration deregulates gene expression but has no consequence on the biology and function of transplanted T cells

Alessandra Recchia, Chiara Bonini, Zulma Magnani, Fabrizia Urbinati, Daniela Sartori, Sara Muraro, Enrico Tagliafico, Attilio Bondanza, Maria Teresa Lupo Stanghellini, Massimo Bernardi, Alessandra Pescarollo, Fabio Ciceri, Claudio Bordignon, Fulvio Mavilio

Research output: Contribution to journalArticle

Abstract

The use of retro viral vectors in gene therapy has raised safety concerns for the genotoxic risk associated with their uncontrolled insertion into the human genome. We have analyzed the consequences of retroviral transduction in T cells from leukemic patients treated with allogeneic stem cell transplantation and donor lymphocytes genetically modified with a suicide gene (HSV-TK). Retroviral vectors integrate preferentially within or near transcribed regions of the genome, with a preference for sequences around promoters and for genes active in T cells at the time of transduction. Quantitative transcript analysis shows that one fifth of these integrations affect the expression of nearby genes. However, transduced T cell populations maintain remarkably stable gene expression profiles, phenotype, biological functions, and immune repertoire in vivo, with no evidence of clonal selection up to 9 yr after administration. Analysis of integrated proviruses in transduced cells before and after transplantation indicates that integrations interfering with normal T cell function are more likely to lead to clonal ablation than expansion in vivo. Despite the potentially dangerous interactions with the T cell genome, retroviral integration has therefore little consequence on the safety and efficacy of T cell transplantation.

Original languageEnglish
Pages (from-to)1457-1462
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number5
DOIs
Publication statusPublished - Jan 31 2006

Keywords

  • Donor lymphocyte infusion
  • Gene therapy
  • Graft-versus-host disease
  • Insertional mutagenesis
  • Retroviral integration

ASJC Scopus subject areas

  • Genetics
  • General

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  • Cite this

    Recchia, A., Bonini, C., Magnani, Z., Urbinati, F., Sartori, D., Muraro, S., Tagliafico, E., Bondanza, A., Stanghellini, M. T. L., Bernardi, M., Pescarollo, A., Ciceri, F., Bordignon, C., & Mavilio, F. (2006). Retroviral vector integration deregulates gene expression but has no consequence on the biology and function of transplanted T cells. Proceedings of the National Academy of Sciences of the United States of America, 103(5), 1457-1462. https://doi.org/10.1073/pnas.0507496103