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rdf:type |
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lifeskim:mentions |
umls-concept:C0023449,
umls-concept:C0034538,
umls-concept:C0037083,
umls-concept:C0038952,
umls-concept:C0079904,
umls-concept:C0205217,
umls-concept:C0332183,
umls-concept:C0683598,
umls-concept:C1314939,
umls-concept:C1516044,
umls-concept:C1521725,
umls-concept:C1704259,
umls-concept:C1705987,
umls-concept:C1710082
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pubmed:issue |
5
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pubmed:dateCreated |
2004-8-19
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pubmed:abstractText |
To investigate possible causes of the variable response to treatment in pediatric B-precursor acute lymphoblastic leukemia (ALL) and to establish potential novel therapeutic targets, we used ionizing radiation (IR) exposure as a model of DNA damage formation to identify tumors with resistance to p53-dependent apoptosis. Twenty-one of 40 ALL tumors responded normally to IR, exhibiting accumulation of p53 and p21 proteins and cleavage of caspases 3, 7, and 9 and of PARP1. Nineteen tumors exhibited apoptotic resistance and lacked PARP1 and caspase cleavage; although 15 of these tumors had normal accumulation of p53 and p21 proteins, examples exhibited abnormal expression of TRAF5, TRAF6, and cIAP1 after IR, suggesting increased NF-kappaB prosurvival signaling as the mechanism of apoptotic resistance. The presence of a hyperactive PARP1 mutation in one tumor was consistent with such increased NF-kappaB activity. PARP1 inhibition restored p53-dependent apoptosis after IR in these leukemias by reducing NF-kappaB DNA binding and transcriptional activity. In the remaining 4 ALL tumors, apoptotic resistance was associated with a TP53 mutation or with defective activation of p53. We conclude that increased NF-kappaB prosurvival signaling is a frequent mechanism by which B-precursor ALL tumors develop apoptotic resistance to IR and that PARP1 inhibition may improve the DNA damage response of these leukemias.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
AIM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Sep
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pubmed:issn |
0006-4971
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pubmed:author |
pubmed-author:AustenBelindaB,
pubmed-author:DarbyshirePhilip JPJ,
pubmed-author:GriffithsMikeM,
pubmed-author:HillFrankF,
pubmed-author:LawsonSarahS,
pubmed-author:MannJill RJR,
pubmed-author:MarstonEliotE,
pubmed-author:MossPaul A HPA,
pubmed-author:StankovicTatjanaT,
pubmed-author:TaylorA Malcolm RAM,
pubmed-author:WeiWenbinW,
pubmed-author:WestonVictoria JVJ,
pubmed-author:YeoG NGN
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pubmed:issnType |
Print
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pubmed:day |
1
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pubmed:volume |
104
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1465-73
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pubmed:dateRevised |
2007-11-15
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pubmed:meshHeading |
pubmed-meshheading:15142883-Adolescent,
pubmed-meshheading:15142883-Apoptosis,
pubmed-meshheading:15142883-B-Lymphocytes,
pubmed-meshheading:15142883-Child,
pubmed-meshheading:15142883-Child, Preschool,
pubmed-meshheading:15142883-Cyclin-Dependent Kinase Inhibitor p21,
pubmed-meshheading:15142883-Cyclins,
pubmed-meshheading:15142883-DNA Damage,
pubmed-meshheading:15142883-Gene Expression Profiling,
pubmed-meshheading:15142883-Humans,
pubmed-meshheading:15142883-Infant,
pubmed-meshheading:15142883-NF-kappa B,
pubmed-meshheading:15142883-Poly(ADP-ribose) Polymerases,
pubmed-meshheading:15142883-Precursor Cell Lymphoblastic Leukemia-Lymphoma,
pubmed-meshheading:15142883-Radiation, Ionizing,
pubmed-meshheading:15142883-Signal Transduction,
pubmed-meshheading:15142883-Tumor Cells, Cultured,
pubmed-meshheading:15142883-Tumor Suppressor Protein p53
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pubmed:year |
2004
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pubmed:articleTitle |
Apoptotic resistance to ionizing radiation in pediatric B-precursor acute lymphoblastic leukemia frequently involves increased NF-kappaB survival pathway signaling.
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pubmed:affiliation |
Cancer Research UK Institute for Cancer Studies, Birmingham University, Edgbaston, Birmingham, B15 2TT, United Kingdom. victoriaw@cancer.bham.ac.uk
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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