ATM Mutations Define a Subset of B-CLL Tumours That Only Partially Correlates with 11q Status and Is Associated with Impaired Patient Survival.

The clinical progression of B cell chronic lymphocytic leukaemia (B-CLL) is heterogeneous and prognostic markers are important both for patient management and understanding of disease biology. Deletions of chromosome 11q are associated with a severe clinical phenotype and reduced survival in CLL but the genetic basis of this association has not been defined. The ATM gene is located within the minimally deleted region on 11q and ATM mutations have been reported in CLL suggesting that it may be acting as a tumour suppressor gene. The prevalence and clinical effects of ATM mutations in an unselected cohort of CLL patients are currently unknown. ATM is a complex protein that senses and coordinates the cellular response to double stranded DNA breaks. This type of damage occurs following exposure to irradiation or chemotherapeutic drugs such as fludarabine. The principal ATM responses include p53 upregulation and activation of apoptosis. We screened a cohort of 150 unselected B-CLL patients for mutations within the ATM and TP53 genes using genomic DNA and denaturing high performance liquid chromatography. ATM mutational status was compared to 11q status and VH status, and the functional analysis of ATM was assessed by ATM auto-phosphorylation and p53 phosphorylation in response to DNA damage. 22 ATM mutations were detected in 17 patients indicating a prevalence of ATM mutations of 12%. The relationship between ATM mutation and chromosome 11q deletion was not absolute, as only 50% of patients with an ATM mutation showed evidence of an 11q deletion whereas 55% of patients carried an 11q deletion without evidence of mutation within the ATM gene. Interestingly, ATM induced phosphorylation responses were able to distinguish 11q deleted B-CLLs with an additional ATM mutation from those with wildtype ATM. Furthermore these responses were also able to distinguish pathogenic ATM mutations from potential polymorphic sequence changes. No relationship was seen between either ATM or 11q status and VH status. The median survival of patients carrying an ATM mutation was 6.5 years compared to 2 years in patients with a TP53 mutation and 12 years in patients without mutations in either gene. The reduced survival in patients with ATM mutations may reflect impairment in the apoptotic response to DNA damage mediated by chemotherapeutic drugs. The observation that the clinical significance of ATM mutation is not as marked as TP53 mutation may reflect partial redundancy in signalling of DNA damage between ATM and other PIKK family members, such as ATR. In summary, we show that mutations in ATM are an important prognostic factor in B-CLL although do not fully correlate with the presence of 11q deletions. Furthermore ATM mutational status can be detected using a functional assay involving specific damage induced phosphorylation events. Patients with ATM mutations have reduced survival and may benefit from novel therapeutic strategies that act through a p53 independent pathway.

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