SEARCH:   Advanced

Prepublished online as a Blood First Edition Paper on April 30, 2002; DOI 10.1182/blood-2002-02-0382. This Article Full Text (PDF) All Versions of this Article: 2002-02-0382v1 100/4/1430    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 Gronbaek, K. Articles by Guldberg, P. Search for Related Content PubMed PubMed Citation Articles by Gronbaek, K. Articles by Guldberg, P. Social Bookmarking                   What's this? Submitted February 5, 2002 Accepted April 10, 2002 ATM mutations are associated with inactivation of the ARF-TP53 tumor suppressor pathway in diffuse large B-cell lymphoma Kirsten Gronbaek, Jesper Worm, Elisabeth Ralfkiaer, Vibeke Ahrenkiel, Peter Hokland, and Per Guldberg* Department of Tumor Cell Biology, Institute of Cancer Biology, Copenhagen, Denmark Department of Pathology, Rigshospitalet, Copenhagen, Denmark; Department of Pathology, Herlev University Hospital, Copenhagen, Denmark Department of Hematology, Aarhus University Hospital, Aarhus, Denmark * Corresponding author; email: perg{at}cancer.dk. The ATM serine-threonine kinase plays a central role in the cellular response to DNA damage. Germ-line mutations in the ATM gene cause ataxia-telangiectasia (A-T), a multisystem disorder associated with predisposition to lymphoma and acute leukemia. Moreover, somatic ATM mutations have been identified in T-cell prolymphocytic leukemia, mantle cell lymphoma, and B-cell chronic lymphocytic leukemia. In this study, the entire ATM coding sequence was examined in genomic DNA from 120 lymphoid neoplasms. Novel mutations and mutations implicated in cancer and/or A-T were found in 9 of 45 diffuse large B-cell lymphomas (DLBCL), 2 of 24 follicular lymphomas, and 1 of 27 adult acute lymphoblastic leukemias, whereas no such mutations were detected among 24 peripheral T-cell lymphomas. The mutational spectrum consisted of 2 nonsense mutations, 1 mutation affecting RNA splicing, and 10 missense variants. Most of these mutations were associated with loss or mutation of the paired ATM allele, consistent with biallelic inactivation of ATM. Seven of the 9 DLBCLs with ATM mutations also carried TP53 mutations and/or deletions of the ARF gene (P = 0.003). The ATM 735C>T substitution previously considered a rare normal variant was found to be 5.6 times more frequent in DLBCL than in random individuals (P = 0.026), suggesting that it may predispose to B-cell lymphoma. Our data suggest that ATM mutations contribute to the development of DLBCL, and that ATM and the ARF-p53 tumor suppressor pathway may cooperate in the pathogenesis of this malignancy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: 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] M. Reimann, C. Loddenkemper, C. Rudolph, I. Schildhauer, B. Teichmann, H. Stein, B. Schlegelberger, B. Dorken, and C. A. Schmitt The Myc-evoked DNA damage response accounts for treatment resistance in primary lymphomas in vivo Blood, October 15, 2007; 110(8): 2996 - 3004. [Abstract] [Full Text] [PDF] C. B. Poulsen, R. Borup, N. Borregaard, F. C. Nielsen, M. B. Moller, and E. Ralfkiaer Prognostic significance of metallothionein in B-cell lymphomas Blood, November 15, 2006; 108(10): 3514 - 3519. [Abstract] [Full Text] [PDF] B. Austen, J. E. Powell, A. Alvi, I. Edwards, L. Hooper, J. Starczynski, A. M. R. Taylor, C. Fegan, P. Moss, and T. Stankovic 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 Blood, November 1, 2005; 106(9): 3175 - 3182. [Abstract] [Full Text] [PDF] A. Kotani, I.-m. Okazaki, M. Muramatsu, K. Kinoshita, N. A. Begum, T. Nakajima, H. Saito, and T. Honjo A target selection of somatic hypermutations is regulated similarly between T and B cells upon activation-induced cytidine deaminase expression PNAS, March 22, 2005; 102(12): 4506 - 4511. [Abstract] [Full Text] [PDF] M. Takagi, R. Tsuchida, K. Oguchi, T. Shigeta, S. Nakada, K. Shimizu, M. Ohki, D. Delia, L. Chessa, Y. Taya, et al. Identification and characterization of polymorphic variations of the ataxia telangiectasia mutated (ATM) gene in childhood Hodgkin disease Blood, January 1, 2004; 103(1): 283 - 290. [Abstract] [Full Text] [PDF] M. Mauget-Faysse, M. Vuillaume, M. Quaranta, N. Moullan, S. Angele, M. D. Friesen, and J. Hall Idiopathic and Radiation-Induced Ocular Telangiectasia: The Involvement of the ATM Gene Invest. Ophthalmol. Vis. Sci., August 1, 2003; 44(8): 3257 - 3262. [Abstract] [Full Text] [PDF] J. Starczynski, W. Simmons, J. R. Flavell, P. J. Byrd, G. S. Stewart, H. S. Kullar, A. Groom, J. Crocker, P. A.H. Moss, G. M. Reynolds, et al. Variations in ATM Protein Expression During Normal Lymphoid Differentiation and Among B-Cell-Derived Neoplasias Am. J. Pathol., August 1, 2003; 163(2): 423 - 432. [Abstract] [Full Text] [PDF] N. Y. Fang, T. C. Greiner, D. D. Weisenburger, W. C. Chan, J. M. Vose, L. M. Smith, J. O. Armitage, R. A. Mayer, B. L. Pike, F. S. Collins, et al. Oligonucleotide microarrays demonstrate the highest frequency of ATM mutations in the mantle cell subtype of lymphoma PNAS, April 29, 2003; 100(9): 5372 - 5377. [Abstract] [Full Text] [PDF]

	Copyright © 2002 by American Society of Hematology         Online ISSN: 1528-0020