TEL/JAK2 tyrosine kinase inhibits DNA repair in the presence of amifostine.
The TEL/JAK2 chromosomal translocation (t(9;12)(p24;p13)) is associated with T cell childhood acute lymphoblastic leukemia. The TEL/JAK2 fusion protein contains the JAK2 catalytic domain and the TEL-specific oligomerization domain. TEL-mediated oligomerization of the TEL/JAK2 proteins results in the constitutive activation of the tyrosine kinase activity. Leukemia cells expressing TEL/JAK2 tyrosine kinase become resistant to anti-neoplastic drugs. Amifostine is a pro-drug which can selectively protect normal tissues against the toxicity of anticancer drugs and radiation. We investigated the effects of amifostine on idarubicin-induced DNA damage and repair in murine pro-B lymphoid BaF3 cells and BaF3-TEL/JAK2-transformed cells using alkaline single cell gel electrophoresis (comet assay). Idarubicin induced DNA damage in both cell types but amifostine reduced its extent in control non-transformed BaF3 cells and enhanced it in TEL/JAK2-transformed cells. The transformed cells did not show measurable DNA repair after exposure to amifostine and idarubicin, but cells treated only with idarubicin were able to recover within a 60-min incubation. Because TEL/JAK2-transformed cells can be considered as model cells for certain human leukemias and lymphomas we anticipate an enhancement of idarubicin cytotoxicity by amifostine in these diseases. Moreover, TEL/JAK2 tyrosine kinase might be involved in cellular response to DNA damage. Amifostine could promote apoptosis or lower the threshold for apoptosis induction dependent on TEL/JAK2 activation.
Department of Molecular Genetics, University of Lódź, Poland.
Ewa
E
Gloc
Mariusz
M
Warszawski
Wojciech
W
Młynarski
Małgorzata
M
Stolarska
Grazyna
G
Hoser
Tomasz
T
Skorski
Janusz
J
Błasiak
D004999:Amifostine / Q000494:pharmacology*; D000818:Animals; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects*; D007700:Kinetics; D007938:Leukemia / Q000188:drug therapy*; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D053614:Janus Kinase 2; D000097764:ETS Translocation Variant 6 Protein
D004999:Amifostine; D015514:Oncogene Proteins, Fusion; C108603:TEL-JAK2 fusion protein, human; D053614:Janus Kinase 2; D000097764:ETS Translocation Variant 6 Protein; C491568:TEL-JAK2 fusion protein, mouse