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Blood, 1 January 2009, Vol. 113, No. 1, pp. 117-126. Prepublished online as a Blood First Edition Paper on October 21, 2008; DOI 10.1182/blood-2008-03-142950. This Article Full Text Full Text (PDF) Supplemental Table and Figures All Versions of this Article: blood-2008-03-142950v1 113/1/117    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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by Marston, E. Articles by Stankovic, T. Search for Related Content PubMed PubMed Citation Articles by Marston, E. Articles by Stankovic, T. Related Collections Lymphoid Neoplasia Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  LYMPHOID NEOPLASIA Stratification of pediatric ALL by in vitro cellular responses to DNA double-strand breaks provides insight into the molecular mechanisms underlying clinical response Eliot Marston1, Victoria Weston1, Jennifer Jesson2, Esther Maina1, Carmel McConville3, Angelo Agathanggelou1, Anna Skowronska1, Katie Mapp3, Katrin Sameith4, Judith E. Powell5, Sarah Lawson2, Pamela Kearns3, Francesco Falciani4, Malcolm Taylor1, and Tatjana Stankovic1 1 Cancer Research UK Institute for Cancer Studies, Birmingham University, Birmingham; 2 Department of Haematology, Birmingham Children's Hospital, Birmingham; 3 Institute for Child Health, University of Birmingham, Birmingham; 4 School of Biosciences and Institute for Biomedical Research, University of Birmingham, Birmingham; and 5 Department of Epidemiology and Public Health, University of Birmingham, Birmingham, United Kingdom The molecular basis of different outcomes in pediatric acute lymphoblastic leukemia (ALL) remains poorly understood. We addressed the clinical significance and mechanisms behind in vitro cellular responses to ionizing radiation (IR)–induced DNA double-strand breaks in 74 pediatric patients with ALL. We found an apoptosis-resistant response in 36% of patients characterized by failure to cleave caspase-3, -7, -9, and PARP1 by 24 hours after IR and an apoptosis-sensitive response with the cleavage of the same substrates in the remaining 64% of leukemias. Resistance to IR in vitro was associated with poor early blast clearance at day 7 or 15 and persistent minimal residual disease (MRD) at day 28 of induction treatment. Global gene expression profiling revealed abnormal up-regulation of multiple prosurvival pathways in response to IR in apoptosis-resistant leukemias and differential posttranscriptional activation of the PI3-Akt pathway was observed in representative resistant cases. Importantly, pharmacologic inhibition of selected prosurvival pathways sensitized apoptosis-resistant ALL cells to IR in vitro. We suggest that abnormal prosurvival responses to DNA damage provide one of the mechanisms of primary resistance in ALL, and that they should be considered as therapeutic targets in children with aggressive disease. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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