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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,{dagger} Agnieszka Bronisz,1,{ddagger} Maciej Malecki,1,&§ Janusz Blasiak,3 Richard Fishel,4 and Tomasz Skorski1*

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.

* Corresponding author. Mailing address: Center for Biotechnology, Bio-Life Sciences Building, Room 419, Temple University, 1900 N. 12th St., Philadelphia, PA 19122. Phone: (215) 204-8847. Fax: (215) 204-1009. E-mail: tskorski{at}astro.temple.edu.

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

{ddagger} 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.

Molecular and Cellular Biology, June 2002, p. 4189-4201, Vol. 22, No. 12
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.12.4189-4201.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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