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

A. Quintás-Cardama, W. Tong, T. Manshouri, F. Vega, P. A. Lennon, J. Cools, D. G. Gilliland, F. Lee, J. Cortes, H. Kantarjian, G. Garcia-Manero

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59 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1117-1124
Number of pages8
JournalLeukemia
Volume22
Issue number6
DOIs
StatePublished - Jun 2008
Externally publishedYes

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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    Quintás-Cardama, A., Tong, W., Manshouri, T., Vega, F., Lennon, P. A., Cools, J., Gilliland, D. G., Lee, F., Cortes, J., Kantarjian, H., & Garcia-Manero, G. (2008). Activity of tyrosine kinase inhibitors against human NUP214-ABL1-positive T cell malignancies. Leukemia, 22(6), 1117-1124. https://doi.org/10.1038/leu.2008.80