Figure 4.
Figure 4. The effects of ATM mutations on the phosphorylation of ATM targets after ionizing irradiation. (A) CLL 35, with no ATM mutations, exhibited induction of ATM and p53 phosphorylation at 15 and 45 minutes after irradiation (IR). CLL 11, with 2 ATM mutations, shows almost no induction of the phosphorylation of either ATM or p53 at both time points after IR. CLL 92, with one ATM mutation, showed no induction in the phosphorylation of ATM but does exhibit some induction in the phosphorylation of p53 after IR. (B) CLLs 155 and 13, with wild-type ATM and no 11q deletion, had a normal ATM-dependent response. CLLs 15 and 7, with an 11q deletion (detected in 95% and 92% of cells respectively) and with an ATM mutation, revealed no ATM protein and no induction of p53 phosphorylation following IR. CLLs 19, 138, 37, and 25, with an 11q deletion (detected in 95%, 80%, 75%, and 97% of cells respectively) and a wild-type ATM allele, all exhibited induction of p53 phosphorylation comparable to wild-type tumors. (C) The induction of phosphorylation of multiple ATM targets is compared between tumor subtypes. Baseline levels of SMC1, Nbs1, and p53 proteins are shown below each phosphorylated protein and are comparable in all tumors. CLL 138, with loss of one ATM allele through an 11q deletion but with a remaining wild-type ATM allele, demonstrated induction of phosphorylation of ATM, p53, SMC1, and Nbs1 at early time points after IR, consistent with normal ATM activity. In contrast, CLLs 199 and 75, with one ATM allele with a missense mutation ATM and one wild-type ATM allele, showed impaired phosphorylation of ATM targets (most marked for CLL 199) despite high ATM protein levels, consistent with a potential dominant-negative effect. CLL 15, with loss of one ATM allele and a mutation in the remaining ATM allele, failed to phosphorylate any of the target proteins consistent with absent ATM protein. (D) CLL 34 had a normal ATM-dependent response. CLL 124, with a mutation in both the ATM and TP53 genes, showed absence of phosphorylation of ATM in response to IR, but increased baseline phosphorylation of p53 that increased further during response to IR.

The effects of ATM mutations on the phosphorylation of ATM targets after ionizing irradiation. (A) CLL 35, with no ATM mutations, exhibited induction of ATM and p53 phosphorylation at 15 and 45 minutes after irradiation (IR). CLL 11, with 2 ATM mutations, shows almost no induction of the phosphorylation of either ATM or p53 at both time points after IR. CLL 92, with one ATM mutation, showed no induction in the phosphorylation of ATM but does exhibit some induction in the phosphorylation of p53 after IR. (B) CLLs 155 and 13, with wild-type ATM and no 11q deletion, had a normal ATM-dependent response. CLLs 15 and 7, with an 11q deletion (detected in 95% and 92% of cells respectively) and with an ATM mutation, revealed no ATM protein and no induction of p53 phosphorylation following IR. CLLs 19, 138, 37, and 25, with an 11q deletion (detected in 95%, 80%, 75%, and 97% of cells respectively) and a wild-type ATM allele, all exhibited induction of p53 phosphorylation comparable to wild-type tumors. (C) The induction of phosphorylation of multiple ATM targets is compared between tumor subtypes. Baseline levels of SMC1, Nbs1, and p53 proteins are shown below each phosphorylated protein and are comparable in all tumors. CLL 138, with loss of one ATM allele through an 11q deletion but with a remaining wild-type ATM allele, demonstrated induction of phosphorylation of ATM, p53, SMC1, and Nbs1 at early time points after IR, consistent with normal ATM activity. In contrast, CLLs 199 and 75, with one ATM allele with a missense mutation ATM and one wild-type ATM allele, showed impaired phosphorylation of ATM targets (most marked for CLL 199) despite high ATM protein levels, consistent with a potential dominant-negative effect. CLL 15, with loss of one ATM allele and a mutation in the remaining ATM allele, failed to phosphorylate any of the target proteins consistent with absent ATM protein. (D) CLL 34 had a normal ATM-dependent response. CLL 124, with a mutation in both the ATM and TP53 genes, showed absence of phosphorylation of ATM in response to IR, but increased baseline phosphorylation of p53 that increased further during response to IR.

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