Expression of dominant-negative Ikaros isoforms in T-cell acute lymphoblastic leukemia

Citation
L. Sun et al., Expression of dominant-negative Ikaros isoforms in T-cell acute lymphoblastic leukemia, CLIN CANC R, 5(8), 1999, pp. 2112-2120
Citations number
18
Categorie Soggetti
Oncology
Journal title
CLINICAL CANCER RESEARCH
ISSN journal
10780432 → ACNP
Volume
5
Issue
8
Year of publication
1999
Pages
2112 - 2120
Database
ISI
SICI code
1078-0432(199908)5:8<2112:EODIII>2.0.ZU;2-K
Abstract
Ikaros, a zinc finger-containing DNA-binding protein, is required for norma l lymphocyte development. Germ-line mutant mice that express only non-DNA b inding dominant-negative "leukemogenic" Ikaros isoforms lacking critical NH 2-terminal zinc fingers develop an aggressive form of T-cell leukemia. We s tudied Ikaros gene expression in leukemic cells from 18 children with T-cel l acute lymphoblastic leukemia (T-ALL). In each of the 18 T-ALL cases as we ll as JK-E6-1 and MOLT-3 cell lines, we found high-level expression of domi nant-negative isoforms of Ikaros with abnormal subcellular compartmentaliza tion patterns. Nuclear extracts from these cells failed to bind to the IKAR OS-specific binding sequence in DNA, PCR cloning and sequencing confirmed t hat JK-E6-1 and MOLT-3 cell lines as well as leukemic cells from 9 of 10 pa tients with T-ATT expressed dominant-negative Ikaros isoforms Ik-4, Ik-7, a nd 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 KSSOPQKFLG) upstream to the transcription activation domain a nd 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-n egative Ikaros isoforms.