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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 (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 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. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 30, 2004 Accepted June 28, 2005 Mutations in the ATM gene lead to impaired overall and treatment free survival of patients with B-CLL that is independent of IGVH mutation status Belinda Austen*, Judith E Powell, Azra Alvi, Ian Edwards, Laura Hooper, Jane Starczynski, A Malcolm R Taylor, Christopher Fegan, Paul Moss, and Tatjana Stankovic CRUK Institute for Cancer Studies, University of Birmingham, Birmingham, United Kingdom Department of Public Health and Epidemiology, University of Birmingham, Birmingham, United Kingdom Haematology, Birmingham Heartlands Hospital, Birmingham, United Kingdom * Corresponding author; email: b.austen{at}bham.ac.uk. The ataxia teleangiectasia 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-CLLs but their clinical significance is unknown. We analysed 155 CLL tumours and found 12% with ATM mutations and 4% with TP53 mutations; two tumours contained mutations in both genes. Retrospective analysis on selected samples indicated that the ATM mutations were usually present at diagnosis. Compared to patients with wild type ATM/TP53 genes, patients with ATM mutations had statistically significantly reduced overall and treatment free survival. Though 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. Tumours with ATM mutations only partially correlated with tumours with loss of an ATM allele through an 11q deletion and, interestingly, those 11q deleted tumours 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: T. Zenz, J. Mohr, E. Eldering, A. P. Kater, A. Buhler, D. Kienle, D. Winkler, J. Durig, M. H. J. van Oers, D. Mertens, et al. miR-34a as part of the resistance network in chronic lymphocytic leukemia Blood, April 16, 2009; 113(16): 3801 - 3808. [Abstract] [Full Text] [PDF] T. J. Kipps Chronic Lymphocytic Leukemia: Advances in Assessing Prognosis and Therapy ASCO Educational Book, January 1, 2009; 2009(1): 385 - 393. [Abstract] [Full Text] [PDF] E. 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