Two transforming C-RAF germ-line mutations identified in patients with therapy-related acute myeloid leukemia.
Cancer Res
; 66(7): 3401-8, 2006 Apr 01.
Article
en En
| MEDLINE
| ID: mdl-16585161
ABSTRACT
Mutations leading to activation of the RAF-mitogen-activated protein kinase/extracellular signal-regulated (ERK) kinase (MEK)-ERK pathway are key events in the pathogenesis of human malignancies. In a screen of 82 acute myeloid leukemia (AML) samples, 45 (55%) showed activated ERK and thus were further analyzed for mutations in B-RAF and C-RAF. Two C-RAF germ-line mutations, S427G and I448V, were identified in patients with therapy-related AML in the absence of alterations in RAS and FLT3. Both exchanges were located within the kinase domain of C-RAF. In vitro and in vivo kinase assays revealed significantly increased activity for (S427G)C-RAF but not for (I448V)C-RAF. The involvement of the S427G C-RAF mutation in constitutive activation of ERK was further confirmed through demonstration of activating phosphorylations on C-RAF, MEK, and ERK in neoplastic cells, but not in nonneoplastic cells. Transformation and survival assays showed oncogenic and antiapoptotic properties for both mutations. Screening healthy individuals revealed a <1/400 frequency of these mutations and, in the case of I448V, inheritance was observed over three generations with another mutation carrier suffering from cancer. Taken together, these data are the first to relate C-RAF mutations to human malignancies. As both mutations are of germ-line origin, they might constitute a novel tumor-predisposing factor.
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Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Leucemia Mieloide
/
Transformación Celular Neoplásica
/
Neoplasias Primarias Secundarias
/
Mutación de Línea Germinal
/
Proteínas Proto-Oncogénicas c-raf
Tipo de estudio:
Prognostic_studies
Límite:
Adult
/
Aged
/
Animals
/
Humans
Idioma:
En
Revista:
Cancer Res
Año:
2006
Tipo del documento:
Article
País de afiliación:
Austria