title: Apoptotic resistance to ionizing radiation in pediatric B-precursor acute lymphoblastic leukemia frequently involves increased NF-kappaB survival pathway signaling.
abstract: 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.
authors.affiliation: Cancer Research UK Institute for Cancer Studies, Birmingham University, Edgbaston, Birmingham, B15 2TT, United Kingdom. victoriaw@cancer.bham.ac.uk
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Weston
authors.forename: Belinda
authors.initials: B
authors.lastname: Austen
authors.forename: Wenbin
authors.initials: W
authors.lastname: Wei
authors.forename: Eliot
authors.initials: E
authors.lastname: Marston
authors.forename: Azra
authors.initials: A
authors.lastname: Alvi
authors.forename: Sarah
authors.initials: S
authors.lastname: Lawson
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Darbyshire
authors.forename: Mike
authors.initials: M
authors.lastname: Griffiths
authors.forename: Frank
authors.initials: F
authors.lastname: Hill
authors.forename: Jill R
authors.initials: JR
authors.lastname: Mann
authors.forename: Paul A H
authors.initials: PA
authors.lastname: Moss
authors.forename: A Malcolm R
authors.initials: AM
authors.lastname: Taylor
authors.forename: Tatjana
authors.initials: T
authors.lastname: Stankovic
mesh_terms: D000293:Adolescent; D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects*; D001402:B-Lymphocytes; D002648:Child; D002675:Child, Preschool; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004249:DNA Damage; D020869:Gene Expression Profiling; D006801:Humans; D007223:Infant; D016328:NF-kappa B / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011839:Radiation, Ionizing; D015398:Signal Transduction / Q000276:immunology / Q000528:radiation effects; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; D011065:Poly(ADP-ribose) Polymerases