This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Koyama, N. Articles by Ottmann, O. G. Search for Related Content PubMed PubMed Citation Articles by Koyama, N. Articles by Ottmann, O. G.

Inhibition of Phosphotyrosine Phosphatase 1B Causes Resistance in BCR-ABL-Positive Leukemia Cells to the ABL Kinase Inhibitor STI571

Authors' Affiliations: ¹ Division of Hematology, Department of Internal Medicine II, Johann Wolfgang Goethe University, Frankfurt, Germany and ² Department of Hematology, Oncology and Transfusion Medicine, University Hospital Benjamin Franklin, Berlin, Germany

Requests for reprints: Oliver Gerhard Ottmann, Department of Hematology and Oncology, University Hospital Frankfurt/Main, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. Phone: 49-69-6301-6365; Fax: 49-69-6301-6089; E-mail: ottmann{at}em.uni-frankfurt.de.

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of BCR-ABL-mediated transformation in vitro and in vivo. To investigate whether PTP1B modulates the biological effects of the abl kinase inhibitor STI571 in BCR-ABL-positive cells, we transfected Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia cell-derived K562 cells with either wild-type PTP1B (K562/PTP1B), a substrate-trapping dominant-negative mutant PTP1B (K562/D181A), or empty vector (K562/mock). Cells were cultured with or without STI571 and analyzed for its effects on proliferation, differentiation, and apoptosis. In both K562/mock and K562/PTP1B cells, 0.25 to 1 µmol/L STI571 induced dose-dependent growth arrest and apoptosis, as measured by a decrease of cell proliferation and an increase of Annexin V-positive cells and/or of cells in the sub-G₁ apoptotic phase. Western blot analysis showed increased protein levels of activated caspase-3 and caspase-8 and induction of poly(ADP-ribose) polymerase cleavage. Low concentrations of STI571 promoted erythroid differentiation of these cells. Conversely, K562/D181A cells displayed significantly lower PTP1B-specific tyrosine phosphatase activity and were significantly less sensitive to STI571-induced growth arrest, apoptosis, and erythroid differentiation. Pharmacologic inhibition of PTP1B activity in wild-type K562 cells, using bis(N,N-dimethylhydroxamido)hydroxooxovanadate, attenuated STI571-induced apoptosis. Lastly, comparison of the STI571-sensitive Ph+ acute lymphoblastic leukemia cell line SupB15 with a STI571-resistant subline revealed significantly decreased PTP1B activity and enhanced BCR-ABL phosphorylation in the STI571-resistant SupB15 cells. In conclusion, functional PTP1B is involved in STI571-induced growth and cell cycle arrest, apoptosis, and differentiation, and attenuation of PTP1B function may contribute to resistance towards STI571.