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Molecular and Cellular Biology, June 2002, p. 4189-4201, Vol. 22, No. 12
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.12.4189-4201.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Fusion Tyrosine Kinases Induce Drug Resistance by Stimulation of Homology-Dependent Recombination Repair, Prolongation of G₂/M Phase, and Protection from Apoptosis

Artur Slupianek,¹ Grazyna Hoser,² Ireneusz Majsterek,^1, Agnieszka Bronisz,^1, Maciej Malecki,^1,& Janusz Blasiak,³ Richard Fishel,⁴ and Tomasz Skorski^1*

Center for Biotechnology, College of Science and Technology, Temple University,¹ Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania,⁴ Department of Clinical Cytobiology, Medical Center for Postgraduate Education, Warsaw,² Department of Molecular Genetics, University of Lodz, Lodz, Poland³

Received 1 August 2001/ Returned for modification 20 September 2001/ Accepted 18 March 2002

Fusion tyrosine kinases (FTKs) such as BCR/ABL, TEL/ABL, TEL/JAK2, TEL/PDGFßR, TEL/TRKC(L), and NPM/ALK arise from reciprocal chromosomal translocations and cause acute and chronic leukemias and non-Hodgkin's lymphoma. FTK-transformed cells displayed drug resistance against the cytostatic drugs cisplatin and mitomycin C. These cells were not protected from drug-mediated DNA damage, implicating activation of the mechanisms preventing DNA damage-induced apoptosis. Various FTKs, except TEL/TRKC(L), can activate STAT5, which may be required to induce drug resistance. We show that STAT5 is essential for FTK-dependent upregulation of RAD51, which plays a central role in homology-dependent recombinational repair (HRR) of DNA double-strand breaks (DSBs). Elevated levels of Rad51 contributed to the induction of drug resistance and facilitation of the HRR in FTK-transformed cells. In addition, expression of antiapoptotic protein Bcl-xL was enhanced in cells transformed by the FTKs able to activate STAT5. Moreover, cells transformed by all examined FTKs displayed G₂/M delay upon drug treatment. Individually, elevated levels of Rad51, Bcl-xL, or G₂/M delay were responsible for induction of a modest drug resistance. Interestingly, combination of these three factors in nontransformed cells induced drug resistance of a magnitude similar to that observed in cells expressing FTKs activating STAT5. Thus, we postulate that RAD51-dependent facilitation of DSB repair, antiapoptotic activity of Bcl-xL, and delay in progression through the G₂/M phase work in concert to induce drug resistance in FTK-positive leukemias and lymphomas.

Present address: Department of Molecular Genetics, University of Lodz, Lodz, Poland.

Present address: Department of Cell Biology, Cancer Center, Warsaw, Poland.

Present address: Laboratory of Molecular Neuropathology, Medical Research Center, Polish Academy of Sciences, Warsaw, Poland.

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