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: Artur Slupianek, Grazyna Hoser, Ireneusz Majsterek, Agnieszka Bronisz, Maciej Malecki, Janusz Blasiak, Richard Fishel, Tomasz Skorski
• Journal: Molecular and cellular biology (Mol Cell Biol) Vol. 22 Issue 12 Pg. 4189-201 (Jun 2002) ISSN: 0270-7306 [Print] United States
• PMID: 12024032 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• BCL2L1 protein, human
• Bcl2l1 protein, mouse
• DNA-Binding Proteins
• Oncogene Proteins, Fusion
• Proto-Oncogene Proteins c-bcl-2
• TEL-ABL fusion protein, human
• TEL-JAK2 fusion protein, human
• TEL-JAK2 fusion protein, mouse
• TEL-PDGFRbeta fusion protein, human
• TEL-TRKC fusion protein, human
• bcl-X Protein
• p80(NPM-ALK) protein
• Protein-Tyrosine Kinases
• Fusion Proteins, bcr-abl
• RAD51 protein, human
• Rad51 Recombinase
• Rad51 protein, mouse

Topics

• Animals
• Apoptosis (drug effects)
• Cell Transformation, Neoplastic
• DNA Repair (drug effects)
• DNA-Binding Proteins (drug effects, genetics, metabolism)
• Drug Resistance (physiology)
• Fusion Proteins, bcr-abl
• G2 Phase (drug effects)
• Humans
• Leukemia (drug therapy, pathology)
• Mice
• Mice, Inbred C57BL
• Mitosis (drug effects)
• Oncogene Proteins, Fusion (drug effects, genetics, metabolism)
• Protein-Tyrosine Kinases (drug effects, genetics, metabolism)
• Proto-Oncogene Proteins c-bcl-2 (drug effects, metabolism)
• Rad51 Recombinase
• Recombination, Genetic
• Tumor Cells, Cultured
• bcl-X Protein