The ataxia telangiectasia mutated (ATM) protein is the principal activator of 
the p53 protein in the response to DNA double-strand breaks. Mutations in the 
ATM gene have been previously found in B-cell chronic lymphocytic leukemias 
(B-CLLs) but their clinical significance is unknown. We analyzed 155 CLL tumors 
and found 12% with ATM mutations and 4% with TP53 mutations; 2 tumors contained 
mutations in both genes. Retrospective analysis on selected samples indicated 
that the ATM mutations were usually present at diagnosis. Compared with patients 
with wild-type ATM/TP53 genes, patients with ATM mutations had statistically 
significantly reduced overall and treatment-free survival. Although present in 
both IGVH mutation subgroups, ATM mutations were associated with unmutated IGVH 
genes and they provided independent prognostic information on multivariate 
analysis. Mutations in the ATM gene resulted in impaired in vitro DNA damage 
responses. Tumors with ATM mutations only partially correlated with tumors with 
loss of an ATM allele through an 11q deletion and, interestingly, those 
11q-deleted tumors with a second wild-type ATM allele had a preserved DNA damage 
response. The majority of patients with ATM mutations were refractory to DNA 
damaging chemotherapeutic drugs and as such might benefit from therapies that 
bypass the ATM/p53 pathway.