Fusion oncogenic tyrosine kinases alter DNA damage and repair after genotoxic treatment: role in drug resistance?
Fusion tyrosine kinases (FTKs) such as BCR/ABL, TEL/ABL, TEL/JAK2, TEL/PDGF beta R 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 gamma-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 gamma-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.
Hoser
Grazyna
G
Department of Clinical Cytobiology, Medical Center for Postgraduate Education, 01-813 Warszawa, Marymoncka 99, Poland.
Majsterek
Ireneusz
I
Romana
Duane L
DL
Slupianek
Artur
A
Blasiak
Janusz
J
Skorski
Tomasz
T
D000818:Animals; D002461:Cell Line, Transformed; D002470:Cell Survival; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005720:Gamma Rays / Q000009:adverse effects; D015255:Idarubicin / Q000494:pharmacology; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D051379:Mice; D009153:Mutagens / Q000627:therapeutic use*; D009363:Neoplasm Proteins / Q000502:physiology; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000502:physiology
D009153:Mutagens; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D008769:Methylnitronitrosoguanidine; D011505:Protein-Tyrosine Kinases; D015255:Idarubicin