Recurrent retroviral vector integration at the Mds1/Evi1 locus in nonhuman primate hematopoietic cells. Blood 2005 Oct 01;106(7):2530-3
Date
06/04/2005Pubmed ID
15933056Pubmed Central ID
PMC1895268DOI
10.1182/blood-2005-03-1115Scopus ID
2-s2.0-25144490586 (requires institutional sign-in at Scopus site) 136 CitationsAbstract
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 over-representation 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.
Author List
Calmels B, Ferguson C, Laukkanen MO, Adler R, Faulhaber M, Kim HJ, Sellers S, Hematti P, Schmidt M, von Kalle C, Akagi K, Donahue RE, Dunbar CEAuthor
Peiman Hematti MD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAntigens, CD34
DNA-Binding Proteins
Disease Progression
Genetic Therapy
Genetic Vectors
Granulocytes
Hematopoiesis
Hematopoietic Stem Cells
Humans
Leukemia
Leukemia Virus, Murine
Leukocytes, Mononuclear
MDS1 and EVI1 Complex Locus Protein
Macaca mulatta
Mutagenesis, Insertional
Primates
Proto-Oncogenes
Retroviridae
Risk
Stem Cells
Time Factors
Transcription Factors
