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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.

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NEOPLASIA

Enhanced phosphorylation of Nbs1, a member of DNA repair/checkpoint complex Mre11-RAD50-Nbs1, can be targeted to increase the efficacy of imatinib mesylate against BCR/ABL-positive leukemia cells

Lori Rink1, Artur Slupianek1, Tomasz Stoklosa2, Margaret Nieborowska-Skorska1, Katarzyna Urbanska3, Ilona Seferynska4, Krzysztof Reiss3, and Tomasz Skorski1

1 Department of Microbiology and Immunology, Temple University, Philadelphia, PA; 2 Department of Immunology, Medical University of Warsaw, Poland; 3 Center for Neurovirology and Cancer Biology, College of Science and Technology, Temple University, Philadelphia, PA; 4 Department of Hematology, Institute of Hematology and Blood Transfusion, Warsaw, Poland

Nbs1, a member of the Mre11-RAD50-Nbs1 complex, is phosphorylated by ATM, the product of the ataxia-telangiectasia mutated gene and a member of the phosphatidylinositol 3-kinase–related family of serine-threonine kinases, 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/PDGFßR, 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 the intra–S-phase checkpoint, decreased homologous recombinational repair (HRR) activity, down-regulated XIAP expression, and sensitized BCR/ABL-positive cells to cytotoxic drugs. Interestingly, inhibition of Nbs1 phosphorylation by S343A mutant enhanced the antileukemia effect of the combination of imatinib and genotoxic agent.


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