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

Abstract

Fusion tyrosine kinases (FTKs) such as BCR/ABL, TEL/ABL, TEL/JAK2, TEL/PDGFβR, 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.

We thank D. Gary Gilliland (Harvard Medical School, Boston, Mass.) and Kristine Yoder (Kimmel Cancer Center, Philadelphia, Pa.) for critical reading of the manuscript.

This work was supported by Public Health Service grant CA89052 from the National Cancer Institute, by American Cancer Society grant RPG-98-348-01-LBC, and by Medical Center for Postgraduate Education grant 501-2-1-03-97/07 (all to T.S.). T.S. is a Scholar of the Leukemia and Lymphoma Society. A.S. is a recipient of the fellowship from the Leukemia Research Foundation and is also supported by a grant from the Elsa U. Pardee Foundation. A.B. and M.M. were recipients of fellowships from the Batory Foundation.