Inhibition of FLT3 in MLL. Validation of a therapeutic target identified by gene expression based classification.
Cancer Cell
; 3(2): 173-83, 2003 Feb.
Article
em En
| MEDLINE
| ID: mdl-12620411
ABSTRACT
We recently found that MLL-rearranged acute lymphoblastic leukemias (MLL) have a unique gene expression profile including high level expression of the receptor tyrosine kinase FLT3. We hypothesized that FLT3 might be a therapeutic target in MLL and found that 5 of 30 MLLs contain mutations in the activation loop of FLT3 that result in constitutive activation. Three are a newly described deletion of I836 and the others are D835 mutations. The recently described FLT3 inhibitor PKC412 proved cytotoxic to Ba/F3 cells dependent upon activated FLT3 containing either mutation. PKC412 is also differentially cytotoxic to leukemia cells with MLL translocations and FLT3 that is activated by either overexpression of the wild-type receptor or mutation. Finally, we developed a mouse model of MLL and used bioluminescent imaging to determine that PKC412 is active against MLL in vivo.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
/
Proto-Oncogenes
/
Proteínas Proto-Oncogênicas
/
Receptores Proteína Tirosina Quinases
/
Estaurosporina
/
Proteínas de Ligação a DNA
/
Leucemia-Linfoma Linfoblástico de Células Precursoras
/
Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Child, preschool
/
Female
/
Humans
Idioma:
En
Revista:
Cancer Cell
Assunto da revista:
NEOPLASIAS
Ano de publicação:
2003
Tipo de documento:
Article
País de afiliação:
Estados Unidos