Fusion oncogenic tyrosine kinases alter DNA damage and repair after genotoxic treatment: role in drug resistance?

Hoser, Grażyna; Majsterek, Ireneusz; Romana, Duane L.; Slupianek, Artur; Blasiak, Janusz; Skorski, Tomasz

« Previous Next »Leukemia Research
Volume 27, Issue 3 , Pages 267-273, March 2003

Fusion oncogenic tyrosine kinases alter DNA damage and repair after genotoxic treatment: role in drug resistance?

Grażyna Hoser
- Department of Clinical Cytobiology, Medical Center for Postgraduate Education, 01-813 Warszawa, Marymoncka 99, Poland
Ireneusz Majsterek
- Department of Molecular Genetics, University of Lodz, 90-237 Lodz, Banacha 12/16, Poland
Duane L. Romana
- Center for Biotechnology, College of Science and Technology, Temple University, Bio-Life Sciences Building, Room 419, Philadelphia, PA 19122, USA
Artur Slupianek
- Center for Biotechnology, College of Science and Technology, Temple University, Bio-Life Sciences Building, Room 419, Philadelphia, PA 19122, USA
Janusz Blasiak
- Department of Molecular Genetics, University of Lodz, 90-237 Lodz, Banacha 12/16, Poland
Tomasz Skorski
- Department of Clinical Cytobiology, Medical Center for Postgraduate Education, 01-813 Warszawa, Marymoncka 99, Poland
- Center for Biotechnology, College of Science and Technology, Temple University, Bio-Life Sciences Building, Room 419, Philadelphia, PA 19122, USA
- Corresponding author. Tel.: +1-215-204-8847; fax: +1-215-204-1009.

Received 25 November 2001; accepted 24 June 2002.

Abstract

Fusion tyrosine kinases (FTKs) such as BCR/ABL, TEL/ABL, TEL/JAK2, TEL/PDGFβR and NPM/ALK arise from reciprocal chromosomal translocations and cause acute and chronic myelogenous leukemias and non-Hodgkin’s lymphoma. Murine hematopoietic growth factor dependent BaF3 cells and cells transformed by FTK (BaF3-FTK) were used to investigate the role of FTKs in response to DNA damage. FTK-transformed cells displayed resistance to genotoxic treatment including γ-radiation and cytostatic agents such as idarubicin and MNNG. More FTK-transformed cells survived genotoxic treatment and were able to proliferate in comparison to parental non-transformed cells. Similar or higher levels of DNA damage was detected in γ-irradiated in BaF3-FTK cells in comparison to BaF3 parental cells. Idarubicin induced different amounts of DNA damage in various BaF3-FTK cells. All BaF3-FTK cells treated with MNNG displayed significantly more DNA damage in comparison to BaF3 cells. Despite the extent of genotoxic effect BaF3-FTK cells were often able to repair damaged DNA more efficiently that the non-transformed counterparts. Inhibition of BCR/ABL kinase activity by STI571 (Gleevec, inatinib mesylate) abrogated the resistance to genotoxic treatment and inhibited DNA repair mechanisms. We hypothesize that facilitation of the DNA repair in FTK-positive cells may contribute to their resistance to genotoxic treatment.

Abbreviations: FTK, fusion tyrosine kinase, NHEJ, non-homologous end-joining repair, HRR, homologous recombination repair, DSBs, double strand breaks, MNNG, N-methyl-N′-nitro-N-nitrozoguanidine

Keywords: BCR/ABL, Drug resistance, DNA damage, DNA repair