Activity of tyrosine kinase inhibitors against human NUP214-ABL1-positive T cell malignancies.
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.
Quintás-Cardama
A
A
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Tong
W
W
Manshouri
T
T
Vega
F
F
Lennon
P A
PA
Cools
J
J
Gilliland
D G
DG
Lee
F
F
Cortes
J
J
Kantarjian
H
H
Garcia-Manero
G
G
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000069439:Dasatinib; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D017404:In Situ Hybridization, Fluorescence; D007942:Leukemia, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009687:Nuclear Proteins / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000378:metabolism; D013844:Thiazoles / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D001549:Benzamides; C082869:CRKL protein; C521114:NUP214-ABL1 fusion protein, human; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D050799:STAT5 Transcription Factor; D013844:Thiazoles; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; C498826:nilotinib; D000069439:Dasatinib