title: Fusion tyrosine kinases induce drug resistance by stimulation of homology-dependent recombination repair, prolongation of G(2)/M phase, and protection from apoptosis.
abstract: Fusion tyrosine kinases (FTKs) such as BCR/ABL, TEL/ABL, TEL/JAK2, TEL/PDGF beta R, 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 G(2)/M delay upon drug treatment. Individually, elevated levels of Rad51, Bcl-xL, or G(2)/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 G(2)/M phase work in concert to induce drug resistance in FTK-positive leukemias and lymphomas.
authors.affiliation: Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania 19122, USA.
authors.forename: Artur
authors.initials: A
authors.lastname: Slupianek
authors.forename: Grazyna
authors.initials: G
authors.lastname: Hoser
authors.forename: Ireneusz
authors.initials: I
authors.lastname: Majsterek
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Bronisz
authors.forename: Maciej
authors.initials: M
authors.lastname: Malecki
authors.forename: Janusz
authors.initials: J
authors.lastname: Blasiak
authors.forename: Richard
authors.initials: R
authors.lastname: Fishel
authors.forename: Tomasz
authors.initials: T
authors.lastname: Skorski
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D004260:DNA Repair / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004351:Drug Resistance / Q000502:physiology*; D016044:Fusion Proteins, bcr-abl; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008938:Mitosis / Q000187:drug effects; D015514:Oncogene Proteins, Fusion / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism; D051135:Rad51 Recombinase; D011995:Recombination, Genetic; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein; D000097764:ETS Translocation Variant 6 Protein; D053614:Janus Kinase 2
chemical_list: D004268:DNA-Binding Proteins; D016044:Fusion Proteins, bcr-abl; D015514:Oncogene Proteins, Fusion; D011505:Protein-Tyrosine Kinases; D019253:Proto-Oncogene Proteins c-bcl-2; D051135:Rad51 Recombinase; D051020:bcl-X Protein; C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; C426234:TEL-ABL fusion protein, human; D000097764:ETS Translocation Variant 6 Protein; C108603:TEL-JAK2 fusion protein, human; D053614:Janus Kinase 2; C491568:TEL-JAK2 fusion protein, mouse; C120888:TEL-PDGFRbeta fusion protein, human; C409037:TEL-TRKC fusion protein, human; C107023:p80(NPM-ALK) protein; C495153:RAD51 protein, human; C495154:Rad51 protein, mouse