1. ¹Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2. ²Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
3. ³School of Health Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
4. ⁴Department of Human Genetics, Flanders Interuniversity Institute for Biotechnology (VIB), Leuven, Belgium
5. ⁵Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
6. ⁶Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA
7. ⁷Bristol-Myers Squibb Oncology, Princeton, NJ, USA

Correspondence: Dr G Garcia-Manero, UT MD Anderson Cancer Center, Department of Leukemia, 1515 Holcombe Blvd, Box 428, Houston, TX 77030, USA. E-mail: ggarciam@mdanderson.org

Received 17 September 2007; Revised 12 February 2008; Accepted 18 February 2008; Published online 10 April 2008.

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.