Abstract |
In T-cell acute lymphoblastic leukemia ( T-ALL), transcription factors are known to be deregulated by chromosomal translocations, but mutations in protein tyrosine kinases have only rarely been identified. Here we describe the extrachromosomal (episomal) amplification of ABL1 in 5 of 90 (5.6%) individuals with T-ALL, an aberration that is not detectable by conventional cytogenetics. Molecular analyses delineated the amplicon as a 500-kb region from chromosome band 9q34, containing the oncogenes ABL1 and NUP214 (refs. 5,6). We identified a previously undescribed mechanism for activation of tyrosine kinases in cancer: the formation of episomes resulting in a fusion between NUP214 and ABL1. We detected the NUP214-ABL1 transcript in five individuals with the ABL1 amplification, in 5 of 85 (5.8%) additional individuals with T-ALL and in 3 of 22 T-ALL cell lines. The constitutively phosphorylated tyrosine kinase NUP214-ABL1 is sensitive to the tyrosine kinase inhibitor imatinib. The recurrent cryptic NUP214-ABL1 rearrangement is associated with increased HOX expression and deletion of CDKN2A, consistent with a multistep pathogenesis of T-ALL. NUP214-ABL1 expression defines a new subgroup of individuals with T-ALL who could benefit from treatment with imatinib.
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Authors | C Graux, J Cools, C Melotte, H Quentmeier, A Ferrando, R Levine, J R Vermeesch, M Stul, B Dutta, N Boeckx, A Bosly, P Heimann, A Uyttebroeck, N Mentens, R Somers, R A F MacLeod, H G Drexler, A T Look, D G Gilliland, L Michaux, P Vandenberghe, I Wlodarska, Peter Marynen, Anne Hagemeijer |
Journal | Nature genetics
(Nat Genet)
Vol. 36
Issue 10
Pg. 1084-9
(Oct 2004)
ISSN: 1061-4036 [Print] United States |
PMID | 15361874
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Benzamides
- DNA, Neoplasm
- Enzyme Inhibitors
- NUP214 protein, human
- Nuclear Pore Complex Proteins
- Piperazines
- Pyrimidines
- Imatinib Mesylate
- Protein-Tyrosine Kinases
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Topics |
- Amino Acid Sequence
- Artificial Gene Fusion
- Base Sequence
- Benzamides
- Cell Line, Tumor
- Chromosomes, Human, Pair 9
(genetics)
- DNA, Neoplasm
(genetics)
- Enzyme Inhibitors
(therapeutic use)
- Gene Amplification
- Genes, abl
- Humans
- Imatinib Mesylate
- In Situ Hybridization, Fluorescence
- Leukemia-Lymphoma, Adult T-Cell
(drug therapy, enzymology, genetics)
- Molecular Sequence Data
- Nuclear Pore Complex Proteins
(genetics)
- Piperazines
(therapeutic use)
- Plasmids
(genetics)
- Protein-Tyrosine Kinases
(antagonists & inhibitors, genetics)
- Pyrimidines
(therapeutic use)
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