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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism
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Adult
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Animals
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Apoptosis / drug effects
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Benzamides
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Blotting, Western
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Cell Cycle / drug effects
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Dasatinib
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Female
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Humans
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Imatinib Mesylate
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In Situ Hybridization, Fluorescence
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Leukemia, Experimental / drug therapy*
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Leukemia, Experimental / enzymology
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Leukemia, Experimental / genetics
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Leukemia-Lymphoma, Adult T-Cell / drug therapy*
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Leukemia-Lymphoma, Adult T-Cell / enzymology
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Leukemia-Lymphoma, Adult T-Cell / genetics
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Male
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Nuclear Proteins / metabolism
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Oncogene Proteins, Fusion / genetics*
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Oncogene Proteins, Fusion / metabolism
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Phosphorylation / drug effects
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Piperazines / therapeutic use
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Protein Kinase Inhibitors / therapeutic use*
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Pyrimidines / therapeutic use
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Reverse Transcriptase Polymerase Chain Reaction
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STAT5 Transcription Factor / metabolism
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Thiazoles / therapeutic use
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Tumor Cells, Cultured
Substances
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Adaptor Proteins, Signal Transducing
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Benzamides
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CRKL protein
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NUP214-ABL1 fusion protein, human
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Nuclear Proteins
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Oncogene Proteins, Fusion
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Piperazines
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Protein Kinase Inhibitors
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Pyrimidines
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STAT5 Transcription Factor
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Thiazoles
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Imatinib Mesylate
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Protein-Tyrosine Kinases
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nilotinib
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Dasatinib