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  • 1
    Keywords: EXPRESSION ; tumor ; CELL ; KINASE ; THERAPY ; TOXICITY ; RISK ; GENE ; gene therapy ; PATIENT ; DOMAIN ; T cell ; T-CELL ; DELETION ; TRIAL ; VECTORS ; DESIGN ; VECTOR ; MUTATION ; leukemia ; ACUTE LYMPHOBLASTIC-LEUKEMIA ; REGION ; MUTATIONS ; EVOLUTION ; TRANSLOCATION ; ABNORMALITIES ; OVEREXPRESSION ; HEMATOPOIETIC-CELLS ; GENE-THERAPY ; insertional mutagenesis ; INTEGRATION ; ENHANCER ; TUMOR-SUPPRESSOR ; THERAPIES ; PROTOCOL ; SEVERE COMBINED IMMUNODEFICIENCY ; SUPPRESSOR ; USA ; CHILD ; ENGLAND ; RECONSTITUTION ; MEDICINE ; SOMATIC MUTATIONS ; UPSTREAM ; VECTOR INTEGRATION ; INSERTION ; ADA ; tumor suppressor ; GENETIC ABNORMALITIES ; Notch1 ; T-CELL DEVELOPMENT ; GAMMA-CHAIN
    Abstract: X-linked SCID (SCID-X1) is amenable to correction by gene therapy using conventional gammaretroviral vectors. Here, we describe the occurrence of clonal T cell acute lymphoblastic leukemia (T-ALL) promoted by insertional mutagenesis in a completed gene therapy trial of 10 SCID-X1 patients. Integration of the vector in an antisense orientation 35 kb upstream of the protooncogene LIM domain only 2 (LMO2) caused overexpression of LMO2 in the leukemic clone. However, leukemogenesis was likely precipitated by the acquisition of other genetic abnormalities unrelated to vector insertion, including a gain-of-function mutation in NOTCH1, deletion of the tumor suppressor gene locus cyclin-dependent kinase 2A (CDKN2A), and translocation of the TCR-beta region to the STIL-TAL1 locus. These findings highlight a general toxicity of endogenous gammaretroviral enhancer elements and also identify a combinatorial process during leukemic evolution that will be important for risk stratification and for future protocol design
    Type of Publication: Journal article published
    PubMed ID: 18688286
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  • 2
    Keywords: CELLS ; EXPRESSION ; proliferation ; SURVIVAL ; tumor ; BLOOD ; CELL ; Germany ; IN-VIVO ; KINASE ; THERAPY ; VIVO ; FOLLOW-UP ; SITE ; SITES ; GENE ; GENE-EXPRESSION ; GENES ; PROTEIN ; PROTEINS ; transcription ; METABOLISM ; TRANSDUCTION ; gene transfer ; GENE-TRANSFER ; PATIENT ; DONOR ; TRANSPLANTATION ; CONTRAST ; SUFFICIENT ; treatment ; FREQUENCY ; FREQUENCIES ; TARGET ; CELL-SURVIVAL ; PATTERNS ; gene expression ; VECTOR ; LYMPHOCYTES ; HUMAN GENOME ; REGION ; REGIONS ; PROGENITOR CELLS ; IMMUNITY ; T-LYMPHOCYTES ; T lymphocyte ; CHILDREN ; PERIPHERAL-BLOOD ; T lymphocytes ; INTEGRATION ; PATTERN ; SEVERE COMBINED IMMUNODEFICIENCY ; LEVEL ; LONG ; progenitor ; EVENTS ; USA ; in vivo ; progenitor cell ; TRANSDUCED CELLS ; RECONSTITUTION ; RETROVIRAL GENE MARKING ; RETROVIRAL INTEGRATION ; MEDICINE ; VECTOR INTEGRATION ; PROGENITOR-CELL ; SCID-X1 ; ADA
    Abstract: We treated 10 children with X-linked SCID (SCID-X1) using gammaretrovirus-mediated gene transfer. Those with sufficient follow-up were found to have recovered substantial immunity in the absence of any serious adverse events up to 5 years after treatment. To determine the influence of vector integration on lymphoid reconstitution, we compared retroviral integration sites (RISs) from peripheral blood CD3(+) T lymphocytes of 5 patients taken between 9 and 30 months after transplantation with transduced CD34(+) progenitor cells derived from 1 further patient and I healthy donor. Integration occurred preferentially in gene regions on either side of transcription start sites, was clustered, and correlated with the expression level in CD34(+) progenitors during transduction. In contrast to those in CD34(+) cells, RISs recovered from engrafted CD3(+)T cells were significantly overrepresented within or near genes encoding proteins with kinase or transferase activity or involved in phosphorus metabolism. Although gross patterns of gene expression were unchanged in transduced cells, the divergence of RIS target frequency between transduced progenitor cells and post-thymic T lymphocytes indicates that vector integration influences cell survival, engraftment, or proliferation
    Type of Publication: Journal article published
    PubMed ID: 17671654
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