TitleIncidence and clinical implications of ATM aberrations in chronic lymphocytic leukemia.
Publication TypeJournal Article
Year of Publication2012
AuthorsOuillette, Peter, Li Jinghui, Shaknovich Rita, Li Yifeng, Melnick Ari, Shedden Kerby, and Malek Sami N.
JournalGenes Chromosomes Cancer
Date Published2012 Dec
KeywordsAtaxia Telangiectasia, Ataxia Telangiectasia Mutated Proteins, Cell Cycle Proteins, Chromosome Deletion, Chromosomes, Human, Pair 11, Cohort Studies, DNA-Binding Proteins, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Mutation, Prospective Studies, Protein Serine-Threonine Kinases, Tumor Suppressor Proteins

<p>A subset of chronic lymphocytic leukemia (CLL) carries mutations in ataxia telangiectasia mutated (ATM). Such ATM mutations may be particularly relevant in the setting of del11q, which invariably results in the deletion of one ATM allele. To improve our understanding of the frequency and type of ATM mutations that exist in CLL, we resequenced all ATM coding exons in 24 CLL with del11q using direct sequencing. We detected two missense mutations, resulting in an ATM mutation frequency of 8%; nonsense and frameshift mutations were not identified. Given the low ATM mutation frequency detected in this cohort, we proceeded with measurements of nonmutational ATM aberrations in CLL through analysis of the activation state of ATM in response to external irradiation. The phosphorylation state of ATM at Ser-1981 was measured using quantitative immunoblotting in purified CLL cells isolated from 251 CLL patients; data were normalized to simultaneous measurements of total ATM protein and actin. Resulting p-ATM/ATM and p-ATM/actin ratios were subsequently analyzed for prognostic significance inclusive and exclusive of TP53 exons 2-10 mutations. From these analyses, conducted in a large prospectively enrolled CLL patient cohort, neither the p-ATM/ATM nor the p-ATM/actin ratios were found to be prognostic for short survival. These data in aggregate demonstrate a low frequency of ATM aberrations in an unselected CLL cohort and do not support a major prognostic role for ATM aberrations in CLL, thus motivating renewed research efforts aimed at understanding the pathobiology of 11q deletions in CLL. © 2012 Wiley Periodicals, Inc.</p>

Alternate JournalGenes Chromosomes Cancer
PubMed ID22952040
PubMed Central IDPMC3465492
Grant ListR01 CA136537 / CA / NCI NIH HHS / United States
CA136537 / CA / NCI NIH HHS / United States