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Blood, 15 July 2007, Vol. 110, No. 2, pp. 651-660. Prepublished online as a Blood First Edition Paper on April 12, 2007; DOI 10.1182/blood-2006-08-042630. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2006-08-042630v1 110/2/651    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Rink, L. Articles by Skorski, T. Search for Related Content PubMed PubMed Citation Articles by Rink, L. Articles by Skorski, T. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 21, 2006 Accepted January 27, 2007 Enhanced phosphorylation of Nbs1, a member of DNA repair/checkpoint complex RAD50-Mre11-Nbs1, can be targeted to increase the efficacy of imatinib mesylate against BCR/ABL-positive leukemia cells Lori Rink, Artur Slupianek, Tomasz Stoklosa, Margaret Nieborowska-Skorska, Katarzyna Urbanska, Ilona Seferynska, Krzysztof Reiss, and Tomasz Skorski* Department of Microbiology & Immunology, Temple University, Philadelphia, PA, United States Department of Immunology, Medical University of Warsaw, Warsaw, Poland Center for Neurovirology & Cancer Biology, College of Science and Technology, Temple University, Philadelphia, PA, United States Department of Hematology, Institute of Hematology and Blood Transfusion, Warsaw, Poland * Corresponding author; email: tskorski{at}temple.edu. Nbs1, a member of the Rad50/Mre11/Nbs1 complex, is phosphorylated by ATM in response to DNA double strand breaks (DSBs) to regulate DNA damage checkpoints. Here we show that BCR/ABL stimulated Nbs1 expression by induction of c-Myc-dependent transactivation and protection from caspase-dependent degradation. BCR/ABL-related fusion tyrosine kinases (FTKs) such as TEL/JAK2, TEL/PDGFR, TEL/ABL, TEL/TRKC, BCR/FGFR1, and NPM/ALK as well as interleukin 3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and stem cell factor (SCF) also stimulated Nbs1 expression. Enhanced ATM kinase-dependent phosphorylation of Nbs1 on Serine 343 (S343) in response to genotoxic treatment was detected in leukemia cells expressing BCR/ABL and other FTKs in comparison to normal counterparts stimulated with IL-3, GM-CSF, and SCF. Expression of Nbs1-S343A mutant disrupted intra S-phase checkpoint, decreased HRR activity, downregulated XIAP expression, and sensitized BCR/ABL-positive cells to cytotoxic drugs. Interestingly, inhibition of Nbs1 phosphorylation by S343A mutant enhanced the anti-leukemia effect of the combination of imatinib and genotoxic agent. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. Choudhury, H. Zhao, F. Jalali, S. AL Rashid, J. Ran, S. Supiot, A. E. Kiltie, and R. G. Bristow Targeting homologous recombination using imatinib results in enhanced tumor cell chemosensitivity and radiosensitivity Mol. Cancer Ther., January 1, 2009; 8(1): 203 - 213. [Abstract] [Full Text] [PDF]

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