Originally published as JCO Early Release 10.1200/JCO.2007.11.2649 on October 29 2007

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Mutation Status of the Residual ATM Allele Is an Important Determinant of the Cellular Response to Chemotherapy and Survival in Patients With Chronic Lymphocytic Leukemia Containing an 11q Deletion

Belinda Austen, Anna Skowronska, Claire Baker, Judith E. Powell, Anne Gardiner, David Oscier, Aneela Majid, Martin Dyer, Reiner Siebert, A. Malcolm Taylor, Paul A. Moss, Tatjana Stankovic

From the Cancer Research UK Institute for Cancer Studies, University of Birmingham; Department of Epidemiology and Public Health, University of Birmingham, Birmingham; Haematology Department, Royal Bournemouth Hospital, Bournemouth; Medical Research Council Toxicology Unit, Leicester University, Leicester, United Kingdom; and Institute for Human Genetics, University Hospital Schleswig-Holstein, Kiel, Germany

Address reprint requests to Tatjana Stankovic, CRUK Institute for Cancer Studies, Vincent Dr, University of Birmingham, Birmingham B15 2TT, United Kingdom; e-mail: t.stankovic{at}bham.ac.uk

Purpose The ataxia telangiectasia mutated (ATM) gene is located on chromosome 11q and loss of this region is common in B-cell chronic lymphocytic leukemia (CLL). Our aim was to determine if CLL tumors with a chromosome 11q deletion might be divided into two subgroups based on the status of the remaining ATM allele.

Methods The sequence of the residual ATM allele was determined in 72 CLLs with an 11q deletion. This was related to the cellular response to irradiation or cytotoxic drug exposure in vitro and clinical outcome.

Results We show that the residual ATM allele is mutated in 36% of CLLs with an 11q deletion and that these leukemias demonstrate an impaired cellular response to irradiation or cytotoxic drug exposure in vitro. Inactivation of the second ATM allele was associated with a reduction in patient survival beyond that already dictated by the presence of an 11q deletion (P = .0283). Furthermore, we demonstrate that ATM mutations may arise during the evolution of an 11q deleted subclone and are associated with its expansion.

Conclusion CLL with 11q deletion can be divided into two subgroups based on the integrity of the residual ATM allele. Patients with complete loss of ATM function, due to biallelic ATM defects, have defective responses to cytotoxic chemotherapeutics in vitro and a poorer clinical outcome. ATM mutant subclones can develop during an individual's disease course and give rise to additional expansion of the 11q deleted subclone.

published online ahead of print at www.jco.org on October 29, 2007.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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