Apoptotic resistance to ionizing radiation in pediatric B-precursor acute lymphoblastic leukemia frequently involves increased NF-kappaB survival pathway signaling.
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.
Weston
Victoria J
VJ
Cancer Research UK Institute for Cancer Studies, Birmingham University, Edgbaston, Birmingham, B15 2TT, United Kingdom. victoriaw@cancer.bham.ac.uk
Austen
Belinda
B
Wei
Wenbin
W
Marston
Eliot
E
Alvi
Azra
A
Lawson
Sarah
S
Darbyshire
Philip J
PJ
Griffiths
Mike
M
Hill
Frank
F
Mann
Jill R
JR
Moss
Paul A H
PA
Taylor
A Malcolm R
AM
Stankovic
Tatjana
T
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
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