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

Author(s): Quintas-Cardama A, Tong W, Manshouri T, Vega F, Lennon PA, Cools J, Gilliland DG, Lee F, Cortes J, Kantarjian H, Garcia-Manero G

Affiliation(s): Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Publication date & source: 2008-06, Leukemia., 22(6):1117-24. Epub 2008 Apr 10.

Publication type: Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

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.

Page last updated: 2008-08-10

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