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.

Abstract

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.

• Authors: 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
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 25 Issue 34 Pg. 5448-57 (Dec 01 2007) ISSN: 1527-7755 [Electronic] United States
• PMID: 17968022 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Cell Cycle Proteins
• DNA-Binding Proteins
• Tumor Suppressor Proteins
• Chlorambucil
• Cyclophosphamide
• ATM protein, human
• Ataxia Telangiectasia Mutated Proteins
• Protein Serine-Threonine Kinases
• Vidarabine
• fludarabine

Topics

• Aged
• Alleles
• Antineoplastic Agents (therapeutic use)
• Ataxia Telangiectasia Mutated Proteins
• Cell Cycle Proteins (genetics, metabolism)
• Chlorambucil (therapeutic use)
• Chromosome Deletion
• Chromosomes, Human, Pair 11
• Cyclophosphamide (therapeutic use)
• DNA Breaks, Double-Stranded
• DNA-Binding Proteins (genetics, metabolism)
• Gene Expression Regulation, Leukemic
• Gene Silencing
• Humans
• Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy, enzymology, genetics)
• Middle Aged
• Mutation
• Phosphorylation (drug effects)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Treatment Outcome
• Tumor Suppressor Proteins (genetics, metabolism)
• Vidarabine (analogs & derivatives, therapeutic use)