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Blood, 1 November 2005, Vol. 106, No. 9, pp. 3175-3182. Prepublished online as a Blood First Edition Paper on July 12, 2005; DOI 10.1182/blood-2004-11-4516. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-11-4516v1 106/9/3175    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Austen, B. Articles by Stankovic, T. Search for Related Content PubMed PubMed Citation Articles by Austen, B. Articles by Stankovic, T. Related Collections Neoplasia Oncogenes and Tumor Suppressors Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Mutations in the ATM gene lead to impaired overall and treatment-free survival that is independent of IGVH mutation status in patients with B-CLL Belinda Austen, Judith E. Powell, Azra Alvi, Ian Edwards, Laura Hooper, Jane Starczynski, A. Malcolm R. Taylor, Christopher Fegan, Paul Moss, and Tatjana Stankovic From the Cancer Research United Kingdom (CRUK) Institute for Cancer Studies and the Department of Public Health and Epidemiology, University of Birmingham, Edgbaston, Birmingham, United Kingdom; and the Department of Haematology, Birmingham Heartlands Hospital, Birmingham, United Kingdom. The ataxia telangiectasia mutated (ATM) protein is the principal activator of the p53 protein in the response to DNA double-strand breaks. Mutations in the ATM gene have been previously found in B-cell chronic lymphocytic leukemias (B-CLLs) but their clinical significance is unknown. We analyzed 155 CLL tumors and found 12% with ATM mutations and 4% with TP53 mutations; 2 tumors contained mutations in both genes. Retrospective analysis on selected samples indicated that the ATM mutations were usually present at diagnosis. Compared with patients with wild-type ATM/TP53 genes, patients with ATM mutations had statistically significantly reduced overall and treatment-free survival. Although present in both IGVH mutation subgroups, ATM mutations were associated with unmutated IGVH genes and they provided independent prognostic information on multivariate analysis. Mutations in the ATM gene resulted in impaired in vitro DNA damage responses. Tumors with ATM mutations only partially correlated with tumors with loss of an ATM allele through an 11q deletion and, interestingly, those 11q-deleted tumors with a second wild-type ATM allele had a preserved DNA damage response. The majority of patients with ATM mutations were refractory to DNA damaging chemotherapeutic drugs and as such might benefit from therapies that bypass the ATM/p53 pathway. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: L. Kujawski, P. Ouillette, H. Erba, C. Saddler, A. Jakubowiak, M. Kaminski, K. Shedden, and S. N. Malek Genomic complexity identifies patients with aggressive chronic lymphocytic leukemia Blood, September 1, 2008; 112(5): 1993 - 2003. [Abstract] [Full Text] [PDF] E. Willmore, S. L. Elliott, T. Mainou-Fowler, G. P. Summerfield, G. H. Jackson, F. O'Neill, C. Lowe, A. Carter, R. Harris, A. R. Pettitt, et al. DNA-Dependent Protein Kinase Is a Therapeutic Target and an Indicator of Poor Prognosis in B-Cell Chronic Lymphocytic Leukemia Clin. Cancer Res., June 15, 2008; 14(12): 3984 - 3992. [Abstract] [Full Text] [PDF] C. Saddler, P. Ouillette, L. Kujawski, S. Shangary, M. Talpaz, M. Kaminski, H. Erba, K. Shedden, S. Wang, and S. N. Malek Comprehensive biomarker and genomic analysis identifies p53 status as the major determinant of response to MDM2 inhibitors in chronic lymphocytic leukemia Blood, February 1, 2008; 111(3): 1584 - 1593. [Abstract] [Full Text] [PDF] B. Austen, A. Skowronska, C. Baker, J. E. Powell, A. Gardiner, D. Oscier, A. Majid, M. Dyer, R. Siebert, A. M. Taylor, et al. Mutation Status of the Residual ATM Allele Is an Important Determinant of the Cellular Response to Chemotherapy and Survival in Patients With Chronic Lymphocytic Leukemia Containing an 11q Deletion J. Clin. Oncol., December 1, 2007; 25(34): 5448 - 5457. [Abstract] [Full Text] [PDF] A. P. Kater, M. H. J. van Oers, and T. J. Kipps Cellular immune therapy for chronic lymphocytic leukemia Blood, October 15, 2007; 110(8): 2811 - 2818. [Abstract] [Full Text] [PDF] A. M. Tsimberidou, S. Wen, S. O'Brien, P. McLaughlin, W. G. Wierda, A. Ferrajoli, S. Faderl, J. Manning, S. Lerner, C. V. Mai, et al. Assessment of Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma by Absolute Lymphocyte Counts in 2,126 Patients: 20 Years of Experience at The University of Texas M.D. Anderson Cancer Center J. Clin. Oncol., October 10, 2007; 25(29): 4648 - 4656. [Abstract] [Full Text] [PDF] A. D. Joshi, G. V. Hegde, J. D. Dickinson, A. K. Mittal, J. C. Lynch, J. D. Eudy, J. O. Armitage, P. J. Bierman, R. G. Bociek, M. P. Devetten, et al. ATM, CTLA4, MNDA, and HEM1 in High versus Low CD38 Expressing B-Cell Chronic Lymphocytic Leukemia Clin. Cancer Res., September 15, 2007; 13(18): 5295 - 5304. [Abstract] [Full Text] [PDF] A. Muntanola, F. Bosch, P. Arguis, E. Arellano-Rodrigo, C. Ayuso, E. Gine, M. Crespo, P. Abrisqueta, C. Moreno, F. Cobo, et al. Abdominal Computed Tomography Predicts Progression in Patients With Rai Stage 0 Chronic Lymphocytic Leukemia J. Clin. Oncol., April 20, 2007; 25(12): 1576 - 1580. [Abstract] [Full Text] [PDF] K. Kojima, M. Konopleva, T. McQueen, S. O'Brien, W. Plunkett, and M. Andreeff Mdm2 inhibitor Nutlin-3a induces p53-mediated apoptosis by transcription-dependent and transcription-independent mechanisms and may overcome Atm-mediated resistance to fludarabine in chronic lymphocytic leukemia Blood, August 1, 2006; 108(3): 993 - 1000. [Abstract] [Full Text] [PDF] X. Jiang, Y. Sun, S. Chen, K. Roy, and B. D. Price The FATC Domains of PIKK Proteins Are Functionally Equivalent and Participate in the Tip60-dependent Activation of DNA-PKcs and ATM J. Biol. Chem., June 9, 2006; 281(23): 15741 - 15746. [Abstract] [Full Text] [PDF] H. E. Bryant and T. Helleday Inhibition of poly (ADP-ribose) polymerase activates ATM which is required for subsequent homologous recombination repair Nucleic Acids Res., March 23, 2006; 34(6): 1685 - 1691. [Abstract] [Full Text] [PDF] C. Mayr, M. R. Speicher, D. M. Kofler, R. Buhmann, J. Strehl, R. Busch, M. Hallek, and C.-M. Wendtner Chromosomal translocations are associated with poor prognosis in chronic lymphocytic leukemia Blood, January 15, 2006; 107(2): 742 - 751. [Abstract] [Full Text] [PDF]

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