|
|
Blood, 1 July 2006, Vol. 108, No. 1, pp. 319-327.
Prepublished online as a Blood First Edition Paper on March 9, 2006; DOI 10.1182/blood-2005-07-2815.
 Previous Article | Next Article 
Submitted July 14, 2005
Accepted February 19, 2006
BCR/ABL kinase induces self-mutagenesis via reactive oxygen species to encode imatinib resistance
Mateusz Koptyra, Rafal Falinski, Michal O Nowicki, Tomasz Stoklosa, Ireneusz Majsterek, Margaret Nieborowska-Skorska, Janusz Blasiak, and Tomasz Skorski*
Department of Microbiology and Immunology, School of Medicine, Temple University, Philadelphia, PA, USA
Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA
Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA; Department of Immunology, The Medical University of Warsaw, Warsaw, Poland
Department of Molecular Genetics, University of Lodz, Lodz, Poland
* Corresponding author; email: tskorski{at}temple.edu.
Mutations in the BCR/ABL kinase domain play a major role in resistance to imatinib mesylate (IM). We report here that BCR/ABL kinase stimulates reactive oxygen species (ROS), which elevate oxidative DNA damage and cause mutations in the kinase domain. The majority of mutations involved A/T G/C and G/CA/T transitions, a phenotype detected previously in patients, which encoded clinically relevant amino acid substitutions causing IM resistance. This effect was reduced in cells expressing BCR/ABL[Y177F] mutant, which does not elevate ROS. Inhibition of ROS in leukemia cells by the anti-oxidants pyrrolidine dithiocarbamate (PDTC), N-acetylcysteine (NAC), and vitamin E (VE) decreased the mutagenesis rate and frequency of IM resistance. Simultaneous administration of IM and an anti-oxidant exerted better anti-mutagenic effect than an anti-oxidant alone. Therefore, inhibition of ROS should diminish mutagenesis and enhance the effectiveness of IM.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
Related Article in Blood Online:
-
Escaping inhibition by self-mutation
- Ravi Bhatia
Blood 2006 108: 7.
[Full Text]
[PDF]
This article has been cited by other articles:
|
|
|
|
 
M. S. Fernandes, M. M. Reddy, J. R. Gonneville, S. C. DeRoo, K. Podar, J. D. Griffin, D. M. Weinstock, and M. Sattler
BCR-ABL promotes the frequency of mutagenic single-strand annealing DNA repair
Blood,
August 27, 2009;
114(9):
1813 - 1819.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Gao, A. Howard, K. Ban, and J. Chandra
Oxidative Stress Promotes Transcriptional Up-regulation of Fyn in BCR-ABL1-expressing Cells
J. Biol. Chem.,
March 13, 2009;
284(11):
7114 - 7125.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Quintas-Cardama and J. Cortes
Molecular biology of bcr-abl1-positive chronic myeloid leukemia
Blood,
February 19, 2009;
113(8):
1619 - 1630.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Hehlmann and S. Saussele
Treatment of chronic myeloid leukemia in blast crisis
Haematologica,
December 1, 2008;
93(12):
1765 - 1769.
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Chevallier, J. Delaunay, P. Turlure, A. Pigneux, M. Hunault, R. Garand, T. Guillaume, H. Avet-Loiseau, N. Dmytruk, S. Girault, et al.
Long-Term Disease-Free Survival After Gemtuzumab, Intermediate-Dose Cytarabine, and Mitoxantrone in Patients With CD33+ Primary Resistant or Relapsed Acute Myeloid Leukemia
J. Clin. Oncol.,
November 10, 2008;
26(32):
5192 - 5197.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Cramer, M. Nieborowska-Skorska, M. Koptyra, A. Slupianek, E. T. P. Penserga, C. J. Eaves, W. Aulitzky, and T. Skorski
BCR/ABL and Other Kinases from Chronic Myeloproliferative Disorders Stimulate Single-Strand Annealing, an Unfaithful DNA Double-Strand Break Repair
Cancer Res.,
September 1, 2008;
68(17):
6884 - 6888.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Stoklosa, T. Poplawski, M. Koptyra, M. Nieborowska-Skorska, G. Basak, A. Slupianek, M. Rayevskaya, I. Seferynska, L. Herrera, J. Blasiak, et al.
BCR/ABL Inhibits Mismatch Repair to Protect from Apoptosis and Induce Point Mutations
Cancer Res.,
April 15, 2008;
68(8):
2576 - 2580.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Mayerhofer, K. V. Gleixner, J. Mayerhofer, G. Hoermann, E. Jaeger, K. J. Aichberger, R. G. Ott, K. Greish, H. Nakamura, S. Derdak, et al.
Targeting of heat shock protein 32 (Hsp32)/heme oxygenase-1 (HO-1) in leukemic cells in chronic myeloid leukemia: a novel approach to overcome resistance against imatinib
Blood,
February 15, 2008;
111(4):
2200 - 2210.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. W.N. Deininger
Imatinib Resistance and the Difficulty of Eradicating Leukemia Stem Cells
ASCO Educational Book,
January 1, 2008;
2008(1):
318 - 323.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Jiang
Toward distinguishing LSCs from HSCs
Blood,
October 1, 2007;
110(7):
2222 - 2223.
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. O'Hare, C. A. Eide, and M. W. N. Deininger
Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia
Blood,
October 1, 2007;
110(7):
2242 - 2249.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. S. Rodrigues and M. Sattler
Chronic Myelogenous Leukemia Progenitors Display a Genetically Unstable Personality
J Natl Cancer Inst,
May 2, 2007;
99(9):
662 - 663.
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Jiang, K. M. Saw, A. Eaves, and C. Eaves
Instability of BCR-ABL Gene in Primary and Cultured Chronic Myeloid Leukemia Stem Cells
J Natl Cancer Inst,
May 2, 2007;
99(9):
680 - 693.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Yoshida, F. Yoshida, D. E. Sears, S. M. Hart, D. Ikebe, A. Muto, S. Basu, K. Igarashi, and J. V. Melo
Bcr-Abl signaling through the PI-3/S6 kinase pathway inhibits nuclear translocation of the transcription factor Bach2, which represses the antiapoptotic factor heme oxygenase-1
Blood,
February 1, 2007;
109(3):
1211 - 1219.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
