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Activity of tyrosine kinase inhibitors against human NUP214-ABL1-positive T cell malignancies.
- Source :
-
Leukemia [Leukemia] 2008 Jun; Vol. 22 (6), pp. 1117-24. Date of Electronic Publication: 2008 Apr 10. - Publication Year :
- 2008
-
Abstract
- Amplification of the NUP214-ABL1 oncogene can be detected in patients with T cell acute lymphoblastic leukemia (T-ALL). We screened 29 patients with T cell malignancies for the expression of NUP214-ABL1 by reverse transcription-polymerase chain reaction (RT-PCR). NUP214-ABL1 was detected in three (10%) patients. These results were confirmed by fluorescence in situ hybridization techniques. We also studied the activity of imatinib, nilotinib and dasatinib against the human NUP214-ABL1-positive cell lines PEER and BE-13. All three tyrosine kinase inhibitors decreased the viability of PEER and BE-13 cells, but nilotinib and dasatinib had >1-log lower IC(50) values than imatinib (P<0.001). In contrast, the NUP214-ABL-negative T-ALL cell line Jurkat, was remarkably resistant to tyrosine kinase inhibition. The inhibition of cellular proliferation was associated with time-dependent induction of apoptosis and inhibition of ABL, CrKL and STAT5 phosphorylation. Moreover, dasatinib was active in a NUP214-ABL1-positive leukemia xenograft murine model and in marrow lymphoblasts from a patient with NUP214-ABL1-positive T-ALL. On the basis of these results, ABL1 kinase inhibitors warrant clinical investigation in patients with NUP214-ABL1-positive T-cell malignancies.
- Subjects :
- Adaptor Proteins, Signal Transducing metabolism
Adult
Animals
Apoptosis drug effects
Benzamides
Blotting, Western
Cell Cycle drug effects
Cell Proliferation drug effects
Cell Survival drug effects
Dasatinib
Female
Humans
Imatinib Mesylate
In Situ Hybridization, Fluorescence
Leukemia, Experimental enzymology
Leukemia, Experimental genetics
Leukemia-Lymphoma, Adult T-Cell enzymology
Leukemia-Lymphoma, Adult T-Cell genetics
Male
Mice
Mice, Inbred NOD
Mice, SCID
Nuclear Proteins metabolism
Oncogene Proteins, Fusion metabolism
Phosphorylation drug effects
Piperazines therapeutic use
Pyrimidines therapeutic use
Reverse Transcriptase Polymerase Chain Reaction
STAT5 Transcription Factor metabolism
Thiazoles therapeutic use
Tumor Cells, Cultured
Leukemia, Experimental drug therapy
Leukemia-Lymphoma, Adult T-Cell drug therapy
Oncogene Proteins, Fusion genetics
Protein Kinase Inhibitors therapeutic use
Protein-Tyrosine Kinases antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5551
- Volume :
- 22
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Leukemia
- Publication Type :
- Academic Journal
- Accession number :
- 18401417
- Full Text :
- https://doi.org/10.1038/leu.2008.80