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The recurrent SET-NUP214fusion as a new HOXAactivation mechanism in pediatric T-cell acute lymphoblastic leukemia
The recurrent SET-NUP214fusion as a new HOXAactivation mechanism in pediatric T-cell acute lymphoblastic leukemia
- Source :
- Blood; May 2008, Vol. 111 Issue: 9 p4668-4680, 13p
- Publication Year :
- 2008
-
Abstract
- T-cell acute lymphoblastic leukemia (T-ALL) is mostly characterized by specific chromosomal abnormalities, some occurring in a mutually exclusive manner that possibly delineate specific T-ALL subgroups. One subgroup, including MLL-rearranged, CALM-AF10or inv (7)(p15q34) patients, is characterized by elevated expression of HOXAgenes. Using a gene expression–based clustering analysis of 67 T-ALL cases with recurrent molecular genetic abnormalities and 25 samples lacking apparent aberrations, we identified 5 new patients with elevated HOXAlevels. Using microarray-based comparative genomic hybridization (array-CGH), a cryptic and recurrent deletion, del (9)(q34.11q34.13), was exclusively identified in 3 of these 5 patients. This deletion results in a conserved SET-NUP214 fusion product, which was also identified in the T-ALL cell line LOUCY. SET-NUP214 binds in the promoter regions of specific HOXAgenes, where it interacts with CRM1 and DOT1L, which may transcriptionally activate specific members of the HOXAcluster. Targeted inhibition of SET-NUP214 by siRNA abolished expression of HOXAgenes, inhibited proliferation, and induced differentiation in LOUCY but not in other T-ALL lines. We conclude that SET-NUP214 may contribute to the pathogenesis of T-ALL by enforcing T-cell differentiation arrest.
Details
- Language :
- English
- ISSN :
- 00064971 and 15280020
- Volume :
- 111
- Issue :
- 9
- Database :
- Supplemental Index
- Journal :
- Blood
- Publication Type :
- Periodical
- Accession number :
- ejs57062459
- Full Text :
- https://doi.org/10.1182/blood-2007-09-111872