High incidence of leukemia in large animals after stem cell gene therapy with a HOXB4-expressing retroviral vector

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High incidence of leukemia in large animals after stem cell gene therapy with a HOXB4-expressing retroviral vector

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dc.contributor.author Zhang, Xiao-Bing en_US
dc.contributor.author Beard, Brian C. en_US
dc.contributor.author Trobridge, Grant D. en_US
dc.contributor.author Wood, Brent L. en_US
dc.contributor.author Sale, George E. en_US
dc.contributor.author Sud, Reeteka en_US
dc.contributor.author Humphries, Keith en_US
dc.contributor.author Kiem, Hans-Peter en_US
dc.date.accessioned 2010-05-06T20:10:11Z
dc.date.available 2010-05-06T20:10:11Z
dc.date.issued 2008-03-20 en_US
dc.identifier.citation Zhang X, Beard BC, Trobridge GD, et al. High incidence of leukemia in large animals after stem cell gene therapy with a HOXB4-expressing retroviral vector . J Clin Invest. 2008;118(4):1502-1510. en_US
dc.identifier.other 10.1172/JCI34371 en_US
dc.identifier.uri http://www.jci.org/articles/view/34371 en_US
dc.identifier.uri http://hdl.handle.net/1773/15882
dc.description.abstract Retroviral vector–mediated HSC gene therapy has been used to treat individuals with a number of life-threatening diseases. However, some patients with SCID-X1 developed retroviral vector–mediated leukemia after treatment. The selective growth advantage of gene-modified cells in patients with SCID-X1 suggests that the transgene may have played a role in leukemogenesis. Here we report that 2 of 2 dogs and 1 of 2 macaques developed myeloid leukemia approximately 2 years after being transplanted with cells that overexpressed homeobox B4 (HOXB4) and cells transduced with a control gammaretroviral vector that did not express HOXB4. The leukemic cells had dysregulated expression of oncogenes, a block in myeloid differentiation, and overexpression of HOXB4. HOXB4 knockdown restored differentiation in leukemic cells, suggesting involvement of HOXB4. In contrast, leukemia did not arise from the cells carrying the control gammaretroviral vector. In addition, leukemia did not arise in 5 animals with high-level marking and polyclonal long-term repopulation following transplantation with cells transduced with an identical gammaretrovirus vector backbone expressing methylguanine methyltransferase. These findings, combined with the absence of leukemia in many other large animals transplanted with cells transduced with gammaretroviral vectors expressing genes other than HOXB4, show that HOXB4 overexpression poses a significant risk of leukemogenesis. Our data thus suggest the continued need for caution in genetic manipulation of repopulating cells, particularly when the transgene might impart an intrinsic growth advantage. en_US
dc.description.sponsorship NIH grants HL53750, HL36444, HL74162, HL84345, DK56465, and DK47754. en_US
dc.language.iso en_US en_US
dc.title High incidence of leukemia in large animals after stem cell gene therapy with a HOXB4-expressing retroviral vector en_US


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