Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients.
J Clin Invest
; 118(9): 3143-50, 2008 Sep.
Article
em En
| MEDLINE
| ID: mdl-18688286
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.
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
/
Tipos_de_cancer
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Outros_tipos
Base de dados:
MEDLINE
Assunto principal:
Terapia Genética
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Imunodeficiência Combinada Severa
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Cromossomos Humanos X
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Leucemia-Linfoma Linfoblástico de Células T Precursoras
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Mutação
Tipo de estudo:
Etiology_studies
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Guideline
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Observational_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Humans
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Infant
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Male
Idioma:
En
Revista:
J Clin Invest
Ano de publicação:
2008
Tipo de documento:
Article
País de afiliação:
Reino Unido