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Blood, 1 September 2004, Vol. 104, No. 5, pp. 1465-1473. Prepublished online as a Blood First Edition Paper on May 13, 2004; DOI 10.1182/blood-2003-11-4039. This Article Full Text (PDF) All Versions of this Article: 2003-11-4039v1 104/5/1465    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 Weston, V. J Articles by Stankovic, T. Search for Related Content PubMed PubMed Citation Articles by Weston, V. J Articles by Stankovic, T. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 25, 2003 Accepted April 22, 2004 Apoptotic resistance to ionising radiation in paediatric B-precursor acute lymphoblastic leukaemia frequently involves increased NF-B survival pathway signalling Victoria J Weston*, Belinda Austen, Wenbin Wei, Eliot Marston, Azra Alvi, Sarah Lawson, Philip J Darbyshire, Mike Griffiths, Frank Hill, Jill R Mann, Paul A Moss, A M Taylor, and Tatjana Stankovic CRUK Institute for Cancer Studies, Birmingham University, Birmingham, United Kingdom Department of Haematology, Birmingham Children's Hospital, Birmingham, United Kingdom West Midlands Regional Genetics Laboratory, Birmingham, United Kingdom * Corresponding author; email: victoriaw{at}cancer.bham.ac.uk. To investigate possible causes of the variable response to treatment in paediatric B-precursor ALL and establish potential novel therapeutic targets, we used ionising radiation (IR) exposure as a model of DNA damage formation to identify tumours with resistance to p53-dependent apoptosis. 21/40 ALLs responded normally to IR, exhibiting accumulation of p53 and p21 proteins and cleavage of caspases 3, 7 and 9 as well as PARP1. 19 tumours exhibited apoptotic resistance and showed absence of PARP1 and caspase cleavage; while 15 of these had normal p53 and p21 protein accumulation, examples exhibited abnormal expression of TRAF5, TRAF6 and cIAP1 following IR, suggesting increased NF-B pro-survival signalling as the mechanism of apoptotic resistance. The presence of a hyperactive PARP1 mutation in one tumour was consistent with such increased NF-B activity. PARP1 inhibition restored p53-dependent apoptosis following IR in these leukaemias by reducing NF-B DNA binding and transcriptional activity. In the remaining 4 ALLs, apoptotic resistance was associated with either a TP53 mutation or defective activation of p53. We conclude that increased NF-B pro-survival signalling is a frequent mechanism by which B-precursor ALL tumours develop apoptotic resistance to IR and that PARP1 inhibition may improve the DNA damage response of these leukaemias. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. K. Kiessling, C. D. Klemke, M. M. Kaminski, I. E. Galani, P. H. Krammer, and K. Gulow Inhibition of Constitutively Activated Nuclear Factor-{kappa}B Induces Reactive Oxygen Species- and Iron-Dependent Cell Death in Cutaneous T-Cell Lymphoma Cancer Res., March 15, 2009; 69(6): 2365 - 2374. [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] D. S. Kim, J. A. Franklyn, A. L. Stratford, K. Boelaert, J. C. Watkinson, M. C. Eggo, and C. J. McCabe Pituitary Tumor-Transforming Gene Regulates Multiple Downstream Angiogenic Genes in Thyroid Cancer J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 1119 - 1128. [Abstract] [Full Text] [PDF] A. Holleman, M. L. den Boer, R. X. de Menezes, M. H. Cheok, C. Cheng, K. M. Kazemier, G. E. Janka-Schaub, U. Gobel, U. B. Graubner, W. E. Evans, et al. The expression of 70 apoptosis genes in relation to lineage, genetic subtype, cellular drug resistance, and outcome in childhood acute lymphoblastic leukemia Blood, January 15, 2006; 107(2): 769 - 776. [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]

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