Abstract
Recently, unusual forms of leukemias have developed as complications following retroviral transfer of potentially therapeutic genes into hematopoietic cells. A crucial component in the pathogenesis of these complications was the upregulation of a cellular proto-oncogene by random insertion of the retroviral gene transfer vector. These findings have great implications for the genetic manipulation of somatic stem cells in medicine. This review discusses the extent to which the random oncogene activation may have required disease-specific stimuli of the transgene and the hematopoietic milieu to become leukemogenic. Based on these considerations, we propose approaches to risk prediction and prevention.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
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Review
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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DNA-Binding Proteins / biosynthesis
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Genetic Therapy / adverse effects*
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Genetic Vectors
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Hematopoietic Stem Cell Transplantation
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Humans
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LIM Domain Proteins
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Leukemia, T-Cell / etiology*
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Leukemia-Lymphoma, Adult T-Cell / etiology
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Metalloproteins / biosynthesis
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Mice
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Mutagenesis, Insertional*
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Proto-Oncogene Mas
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Proto-Oncogene Proteins
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Proto-Oncogenes / genetics
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Retroviridae / genetics*
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Risk Assessment
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Up-Regulation / genetics
Substances
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Adaptor Proteins, Signal Transducing
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DNA-Binding Proteins
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LIM Domain Proteins
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LMO2 protein, human
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Lmo2 protein, mouse
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MAS1 protein, human
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Metalloproteins
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Proto-Oncogene Mas
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Proto-Oncogene Proteins