Stem Cell Gene Transfer: Insights into Integration and Hematopoiesis from Primate Genetic Marking Studies

Authors

  • CYNTHIA E. DUNBAR

    Corresponding author
    1. Molecular Hematopoiesis Section, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892-1202, USA
    • Address for correspondence: Cynthia E. Dunbar, M.D., Molecular Hematopoiesis Section, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, 10 Center Drive, Building 10 CRC, Room 4E-5132, Bethesda, MD 20892-1202. Voice: 301-496-1434; fax: 301-594-1290. dunbarc@nhlbi.nih.gov

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Abstract

Abstract: Genetic marking strategies in the nonhuman primate model have elucidated a number of principles with relevance to implementation of clinical stem cell therapies, including the lineage potential, number, and life span of hematopoietic stem and progenitor cells. The recent occurrence of leukemias likely related to insertional activation of a proto-oncogene in two patients with X-severe combined immunodeficiency (SCID) syndromes treated with CD34+ cells transduced with retroviral vectors expressing the corrective common γ cytokine receptor gene has refocused attention on the issue of retroviral integration. We have analyzed >1500 independent insertions from rhesus macaques transplanted with CD34+ cells transduced with either MLV or SIV vectors. Of these, 46 rhesus macaques followed long term have not had progression to leukemia, abnormal hematopoiesis, or clonal hematopoiesis. However, the pattern of both MLV and SIV integrants in cells of these animals was found to be highly nonrandom, with a propensity for insertions of both vectors within genes: for MLV particularly near the transcription start site, and for SIV particularly in gene-dense regions.

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