Activity of tyrosine kinase inhibitors against human NUP214-ABL1-positive T cell malignancies

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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 IC50 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.

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