SEARCH:   Advanced

Prepublished online as a Blood First Edition Paper on September 4, 2003; DOI 10.1182/blood-2003-04-1161. This Article Full Text (PDF) All Versions of this Article: 2003-04-1161v1 103/1/291    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 Stankovic, T. Articles by Taylor, A M. R Search for Related Content PubMed PubMed Citation Articles by Stankovic, T. Articles by Taylor, A M. R Social Bookmarking                   What's this? Submitted May 2, 2003 Accepted August 5, 2003 Microarray analysis reveals that TP53 and ATM mutant B-CLLs share a defect in activation of pro-apoptotic responses following DNA damage but are distinguished by major differences in activation of pro-survival responses Tatjana Stankovic*, Mike Hubank, Debbie Cronin, Grant S Stewart, Danielle Fletcher, Colin R Bignell, Azra J Alvi, Belinda Austen, Victoria J Weston, Christopher Fegan, Philip J Byrd, Paul A H Moss, and A Malcolm R Taylor Cancer Research UK Institute for Cancer Studies, University of Birmingham, Birmingham, United Kingdom Department of Molecular Haematology, Institute of Child Health, University College London, London, United Kingdom Department of Hematology, Birmingham Heartlands Hospital, Birmingham, United Kingdom * Corresponding author; email: t.stankovic{at}bham.ac.uk. The ATM/p53 dependent DNA damage response pathway plays an important role in the progression of lymphoid tumours. Inactivation of the ATM or TP53 gene is frequent in B cell lymphocytic leukaemia (B- CLL) and leads to aggressive disease. Although the ATM and p53 pathways are overlapping they are not congruent and it is not clear how the mechanism of tumour progression differs between ATM and p53 deficient tumours. Using microarray analysis of ATM mutant, TP53 mutant and ATM/TP53 wild type B-CLLs we show that following exposure to DNA damage transcriptional responses are entirely dependent on ATM function. The p53 pro-apoptotic responses comprise only a part of ATM regulated transcription and additionally ATM regulates pro-survival responses independently of p53. Consequently, the greater severity of the TP53 mutant B-CLLs compared with ATM mutant B-CLLs is consistent with the additive effect of defective apoptotic and elevated survival responses following DNA damage in these tumours. We also show that transcription expression profiles of ATM deficient, TP53 deficient and wild type B-CLLs are indistinguishable before irradiation. Therefore, damage induced transcriptional fingerprinting can be used to stratify tumours according to their biological differences and simultaneously identify potential targets for treatment of refractory tumours. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: T. Zenz, S. Habe, T. Denzel, J. Mohr, D. Winkler, A. Buhler, A. Sarno, S. Groner, D. Mertens, R. Busch, et al. Detailed analysis of p53 pathway defects in fludarabine-refractory chronic lymphocytic leukemia (CLL): dissecting the contribution of 17p deletion, TP53 mutation, p53-p21 dysfunction, and miR34a in a prospective clinical trial Blood, September 24, 2009; 114(13): 2589 - 2597. [Abstract] [Full Text] [PDF] K. Yoshiyama, P. A. Conklin, N. D. Huefner, and A. B. Britt Suppressor of gamma response 1 (SOG1) encodes a putative transcription factor governing multiple responses to DNA damage PNAS, August 4, 2009; 106(31): 12843 - 12848. [Abstract] [Full Text] [PDF] 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] D. Rossi, M. Cerri, C. Deambrogi, E. Sozzi, S. Cresta, S. Rasi, L. De Paoli, V. Spina, V. Gattei, D. Capello, et al. The Prognostic Value of TP53 Mutations in Chronic Lymphocytic Leukemia Is Independent of Del17p13: Implications for Overall Survival and Chemorefractoriness Clin. Cancer Res., February 1, 2009; 15(3): 995 - 1004. [Abstract] [Full Text] [PDF] E. Marston, V. Weston, J. Jesson, E. Maina, C. McConville, A. Agathanggelou, A. Skowronska, K. Mapp, K. Sameith, J. E. Powell, et al. Stratification of pediatric ALL by in vitro cellular responses to DNA double-strand breaks provides insight into the molecular mechanisms underlying clinical response Blood, January 1, 2009; 113(1): 117 - 126. [Abstract] [Full Text] [PDF] K. Sameith, P. Antczak, E. Marston, N. Turan, D. Maier, T. Stankovic, and F. Falciani Functional modules integrating essential cellular functions are predictive of the response of leukaemia cells to DNA damage Bioinformatics, November 15, 2008; 24(22): 2602 - 2607. [Abstract] [Full Text] [PDF] A. J. Steele, A. G. Prentice, A. V. Hoffbrand, B. C. Yogashangary, S. M. Hart, E. P. Nacheva, J. D. Howard-Reeves, V. M. Duke, P. D. Kottaridis, K. Cwynarski, et al. p53-mediated apoptosis of CLL cells: evidence for a transcription-independent mechanism Blood, November 1, 2008; 112(9): 3827 - 3834. [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] G. S. Sellick, R. Wade, S. Richards, D. G. Oscier, D. Catovsky, and R. S. Houlston Scan of 977 nonsynonymous SNPs in CLL4 trial patients for the identification of genetic variants influencing prognosis Blood, February 1, 2008; 111(3): 1625 - 1633. [Abstract] [Full Text] [PDF] E. Gine, M. Crespo, A. Muntanola, E. Calpe, M. J. Baptista, N. Villamor, E. Montserrat, and F. Bosch Induction of histone H1.2 cytosolic release in chronic lymphocytic leukemia cells after genotoxic and non-genotoxic treatment Haematologica, January 1, 2008; 93(1): 75 - 82. [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] B. A. Olofsson, C. M. Kelly, J. Kim, S. M. Hornsby, and J. Azizkhan-Clifford Phosphorylation of Sp1 in Response to DNA Damage by Ataxia Telangiectasia-Mutated Kinase Mol. Cancer Res., December 1, 2007; 5(12): 1319 - 1330. [Abstract] [Full Text] [PDF] T. Zhou, J. Chou, Y. Zhou, D. A. Simpson, F. Cao, P. R. Bushel, R. S. Paules, and W. K. Kaufmann Ataxia Telangiectasia-Mutated Dependent DNA Damage Checkpoint Functions Regulate Gene Expression in Human Fibroblasts Mol. Cancer Res., August 1, 2007; 5(8): 813 - 822. [Abstract] [Full Text] [PDF] L. A. Smit, D. Y.H. Hallaert, R. Spijker, B. de Goeij, A. Jaspers, A. P. Kater, M. H.J. van Oers, C. J.M. van Noesel, and E. Eldering Differential Noxa/Mcl-1 balance in peripheral versus lymph node chronic lymphocytic leukemia cells correlates with survival capacity Blood, February 15, 2007; 109(4): 1660 - 1668. [Abstract] [Full Text] [PDF] F. Dicker, A. P. Kater, C. E. Prada, T. Fukuda, J. E. Castro, G. Sun, J. Y. Wang, and T. J. Kipps CD154 induces p73 to overcome the resistance to apoptosis of chronic lymphocytic leukemia cells lacking functional p53 Blood, November 15, 2006; 108(10): 3450 - 3457. [Abstract] [Full Text] [PDF] L. Coll-Mulet, D. Iglesias-Serret, A. F. Santidrian, A. M. Cosialls, M. de Frias, E. Castano, C. Campas, M. Barragan, A. F. de Sevilla, A. Domingo, et al. MDM2 antagonists activate p53 and synergize with genotoxic drugs in B-cell chronic lymphocytic leukemia cells Blood, May 15, 2006; 107(10): 4109 - 4114. [Abstract] [Full Text] [PDF] R. A. Gladdy, L. M.J. Nutter, T. Kunath, J. S. Danska, and C. J. Guidos p53-Independent Apoptosis Disrupts Early Organogenesis in Embryos Lacking Both Ataxia-Telangiectasia Mutated and Prkdc Mol. Cancer Res., May 1, 2006; 4(5): 311 - 318. [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] E. Montserrat, C. Moreno, J. Esteve, A. Urbano-Ispizua, E. Gine, and F. Bosch How I treat refractory CLL Blood, February 15, 2006; 107(4): 1276 - 1283. [Abstract] [Full Text] [PDF] T. C. Greiner, C. Dasgupta, V. V. Ho, D. D. Weisenburger, L. M. Smith, J. C. Lynch, J. M. Vose, K. Fu, J. O. Armitage, R. M. Braziel, et al. Mutation and genomic deletion status of ataxia telangiectasia mutated (ATM) and p53 confer specific gene expression profiles in mantle cell lymphoma PNAS, February 14, 2006; 103(7): 2352 - 2357. [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] D. L. Kienle, C. Korz, B. Hosch, A. Benner, D. Mertens, A. Habermann, A. Krober, U. Jager, P. Lichter, H. Dohner, et al. Evidence for Distinct Pathomechanisms in Genetic Subgroups of Chronic Lymphocytic Leukemia Revealed by Quantitative Expression Analysis of Cell Cycle, Activation, and Apoptosis-Associated Genes J. Clin. Oncol., June 1, 2005; 23(16): 3780 - 3792. [Abstract] [Full Text] [PDF] A. J. Alvi, B. Austen, V. J. Weston, C. Fegan, D. MacCallum, A. Gianella-Borradori, D. P. Lane, M. Hubank, J. E. Powell, W. Wei, et al. A novel CDK inhibitor, CYC202 (R-roscovitine), overcomes the defect in p53-dependent apoptosis in B-CLL by down-regulation of genes involved in transcription regulation and survival Blood, June 1, 2005; 105(11): 4484 - 4491. [Abstract] [Full Text] [PDF] U. K. Mukhopadhyay, A. M. Senderowicz, and G. Ferbeyre RNA Silencing of Checkpoint Regulators Sensitizes p53-Defective Prostate Cancer Cells to Chemotherapy while Sparing Normal Cells Cancer Res., April 1, 2005; 65(7): 2872 - 2881. [Abstract] [Full Text] [PDF] C. Haslinger, N. Schweifer, S. Stilgenbauer, H. Dohner, P. Lichter, N. Kraut, C. Stratowa, and R. Abseher Microarray Gene Expression Profiling of B-Cell Chronic Lymphocytic Leukemia Subgroups Defined by Genomic Aberrations and VH Mutation Status J. Clin. Oncol., October 1, 2004; 22(19): 3937 - 3949. [Abstract] [Full Text] [PDF]

	Copyright © 2003 by American Society of Hematology         Online ISSN: 1528-0020