title: 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: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.affiliation: Cancer Research UK Institute for Cancer Studies, University of Birmingham, United Kingdom.
authors.forename: Belinda
authors.initials: B
authors.lastname: Austen
authors.forename: Anna
authors.initials: A
authors.lastname: Skowronska
authors.forename: Claire
authors.initials: C
authors.lastname: Baker
authors.forename: Judith E
authors.initials: JE
authors.lastname: Powell
authors.forename: Anne
authors.initials: A
authors.lastname: Gardiner
authors.forename: David
authors.initials: D
authors.lastname: Oscier
authors.forename: Aneela
authors.initials: A
authors.lastname: Majid
authors.forename: Martin
authors.initials: M
authors.lastname: Dyer
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
authors.forename: A Malcolm
authors.initials: AM
authors.lastname: Taylor
authors.forename: Paul A
authors.initials: PA
authors.lastname: Moss
authors.forename: Tatjana
authors.initials: T
authors.lastname: Stankovic
mesh_terms: D000368:Aged; D000483:Alleles; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002699:Chlorambucil / Q000627:therapeutic use; D002872:Chromosome Deletion; D002880:Chromosomes, Human, Pair 11; D003520:Cyclophosphamide / Q000627:therapeutic use; D053903:DNA Breaks, Double-Stranded; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D020868:Gene Silencing; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D014740:Vidarabine / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D002699:Chlorambucil; D003520:Cyclophosphamide; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D014740:Vidarabine; C024352:fludarabine