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Molecular Targets for Therapy

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

Leukemia volume 22, pages 1117–1124 (2008)Cite this article

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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Acknowledgements

This work was supported by The University of Texas MD Anderson Cancer Center's Physician Scientist Program Award funded by the Commonwealth Cancer Foundation for Research, by The Leukemia and Lymphoma Society of America, and by NIH Grants CA100067 and CA105771 (all to G G-M). Sequencing performed at the core sequencing facility at the University of Texas MD Anderson Cancer Center was funded by Grant CA16672.

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Authors and Affiliations

  1. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    A Quintás-Cardama, W Tong, T Manshouri, J Cortes, H Kantarjian & G Garcia-Manero

  2. Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    F Vega

  3. School of Health Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    P A Lennon

  4. Department of Human Genetics, Flanders Interuniversity Institute for Biotechnology (VIB), Leuven, Belgium

    J Cools

  5. Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA

    D G Gilliland

  6. Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA

    D G Gilliland

  7. Bristol-Myers Squibb Oncology, Princeton, NJ, USA

    F Lee

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  1. A Quintás-Cardama
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Correspondence to G Garcia-Manero.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Quintás-Cardama, A., Tong, W., Manshouri, T. et al. Activity of tyrosine kinase inhibitors against human NUP214-ABL1-positive T cell malignancies. Leukemia 22, 1117–1124 (2008). https://doi.org/10.1038/leu.2008.80

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