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We have previously shown correction of X-linked severe combined immunodeficiency [SCID-X1, also known as gamma chain (gamma(c)) deficiency] in 9 out of 10 patients by retrovirus-mediated gamma(c) gene transfer into autologous CD34 bone marrow cells. However, almost 3 years after gene therapy, uncontrolled exponential clonal proliferation of mature T cells (with gammadelta+ or alphabeta+ T cell receptors) has occurred in the two youngest patients. Both patients' clones showed retrovirus vector integration in proximity to the LMO2 proto-oncogene promoter, leading to aberrant transcription and expression of LMO2. Thus, retrovirus vector insertion can trigger deregulated premalignant cell proliferation with unexpected frequency, most likely driven by retrovirus enhancer activity on the LMO2 gene promoter.

Original publication

DOI

10.1126/science.1088547

Type

Journal article

Journal

Science

Publication Date

17/10/2003

Volume

302

Pages

415 - 419

Keywords

Adaptor Proteins, Signal Transducing, Clinical Trials as Topic, Clone Cells, DNA-Binding Proteins, Gene Expression Regulation, Gene Transfer Techniques, Genetic Therapy, Genetic Vectors, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells, Humans, Infant, LIM Domain Proteins, Leukemia-Lymphoma, Adult T-Cell, Metalloproteins, Mutagenesis, Insertional, Promoter Regions, Genetic, Proto-Oncogene Proteins, Proto-Oncogenes, Receptors, Interleukin-2, Retroviridae, Severe Combined Immunodeficiency, T-Lymphocytes, Transcription, Genetic, Virus Integration, Virus Replication