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Recurrent retroviral vector integration at the Mds1/Evi1 locus in nonhuman primate hematopoietic cells

  1. Author:
    Calmels, B.
    Ferguson, C.
    Laukkanen, M. O.
    Adler, R.
    Faulhaber, M.
    Kim, H. J.
    Sellers, S.
    Hematti, P.
    Schmidt, M.
    von Kalle, C.
    Akagi, K.
    Donahue, R. E.
    Dunbar, C. E.

  2. Author Address

    NHLBI, Hematol Branch, Bethesda, MD 20892 USA. Chonnam Natl Univ Hosp, Kwangju, South Korea. Univ Freiburg, D-7800 Freiburg, Germany. Childrens Hosp Res Fdn, Cincinnati, OH 45229 USA. NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21701 USA Dunbar, CE, NIH, CRC, Bldg 10,Room 4E-5132,10 Ctr Dr, Bethesda, MD 20892 USA
    1. Year: 2005
    2. Date: OCT 1
  2. Journal: Blood
    1. 106
    2. 7
    3. Pages: 2530-2533
  4. Type of Article: Article
  1. Abstract:

    Recent reports linking insertional activation of LMO2 following gene therapy for X-linked severe combined immunodeficiency (X-SCID) have led to a re-evaluation of risks following gene therapy with retroviral vectors. In our analysis of 702 integration sites in rhesus macaques that underwent transplantation up to 7 years earlier with autologous CD34(+) cells transduced with amphotropic murine leukemia virus (MLV)-derived retroviral vectors containing marker genes, we detected insertion into one locus, the Mds1/Evi1 region, a total of 14 times in 9 animals. Mds1/Evi1 integrations were observed stably long term, primarily in myeloid cells. We hypothesize that this overrepresentation likely results from an impact on the self-renewal and engraftment potential of CD34(+) progenitor cells via insertional mutagenesis at this specific locus. There is no evidence of ongoing in vivo clonal expansion of the Mds1/Evi1 populations, and all animals are hematologically normal without evidence for leukemia. Characterization of integration sites in this relevant preclinical model provides critical information for gene therapy risk assessment as well as identification of genes controlling hematopoiesis

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External Sources

  1. View record in Web of Science®
  2. WOS: 000232134700052

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