Defect in cellular responses in

ATM mutant B-CLLs linking IR-induced p53 defect with resistance to apoptosis. (A) The rate of apoptosis after exposure to 5 Gy gamma irradiation was compared in B-CLL tumors either withATM mutations, TP53 mutations, or with wild-typeTP53/ATM sequence. Mean levels of apoptosis induced by ionizing radiation in B-CLLs with wild-type ATM (B-CLLs 13, 19, and 54), mutant ATM (B-CLLs 1, 2, 33, and 34), and also mutant p53 (B-CLLs 9 and 43) up to 6 days after irradiation. In unirradiated B-CLL cells the level of apoptosis was indistinguishable between the different genotypes at all 4 time points (data not shown). (B) Phosphorylation at serine-15 of p53 in B-CLLs 20, 13, 19, and 54 with wild-type ATM but not in B-CLLs 33 and 34 with mutantATM, or in TP53 mutant B-CLL 9 at 0 hours and 10 hours following irradiation. (C) Expression of TRAIL-R2 at 0, 2, 4, 6, 8, and 10 hours following IR with 5 Gy. Up-regulation reaches a peak 10 hours after irradiation in B-CLL20 with wild-type ATM. ATM mutant B-CLL 1 failed to up-regulate TRAIL-R2 following irradiation.