Expression of dominant-negative Ikaros isoforms in T-cell acute lymphoblastic leukemia.
Clin Cancer Res
; 5(8): 2112-20, 1999 Aug.
Article
en En
| MEDLINE
| ID: mdl-10473095
ABSTRACT
Ikaros, a zinc finger-containing DNA-binding protein, is required for normal lymphocyte development. Germ-line mutant mice that express only non-DNA binding dominant-negative "leukemogenic" Ikaros isoforms lacking critical NH2-terminal zinc fingers develop an aggressive form of T-cell leukemia. We studied Ikaros gene expression in leukemic cells from 18 children with T-cell acute lymphoblastic leukemia (T-ALL). In each of the 18 T-ALL cases as well as JK-E6-1 and MOLT-3 cell lines, we found high-level expression of dominant-negative isoforms of Ikaros with abnormal subcellular compartmentalization patterns. Nuclear extracts from these cells failed to bind to the IKAROS-specific binding sequence in DNA. PCR cloning and sequencing confirmed that JK-E6-1 and MOLT-3 cell lines as well as leukemic cells from 9 of 10 patients with T-ALL expressed dominant-negative Ikaros isoforms Ik-4, Ik-7, and Ik-8 that lack critical NH2-terminal zinc fingers. In 6 of 10 patients, we detected a specific mutation leading to an in-frame deletion of 10 amino acids (delta KSSMPQKFLG) upstream to the transcription activation domain and adjacent to the COOH-terminal zinc fingers of Ik-2, Ik-4, Ik-7, and Ik-8. Thus, children with T-ALL express high levels of dysfunctional dominant-negative Ikaros isoforms.
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Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Factores de Transcripción
/
Leucemia-Linfoma de Células T del Adulto
/
Proteínas de Unión al ADN
/
Genes Dominantes
Límite:
Adult
/
Child
/
Child, preschool
/
Female
/
Humans
/
Infant
/
Male
Idioma:
En
Revista:
Clin Cancer Res
Asunto de la revista:
NEOPLASIAS
Año:
1999
Tipo del documento:
Article
País de afiliación:
Estados Unidos