title: Ataxia-telangiectasia and T-cell leukemias: no evidence for somatic ATM mutation in sporadic T-ALL or for hypermethylation of the ATM-NPAT/E14 bidirectional promoter in T-PLL.
abstract: The ATM gene deficient in ataxia-telangiectasia, a recessive multisystem disease associated with a high risk of lymphomas and leukemias, was found previously to be inactivated in a rare sporadic malignancy, T-cell prolymphocytic leukemia (T-PLL), which is often associated with cytogenetic aberrations of chromosome 14. The ATM gene was shown to sustain frequent loss-of-function mutations in T-PLL tumor cells, consistent with functioning as a tumor suppressor gene in this leukemia. To investigate the possibility of nonmutational or nonrecombinational mechanisms of T-PLL development, we have used bisulfite genomic sequencing to analyze DNA methylation in the putative bidirectional promoter region of the closely linked ATM and NPAT/E14 genes within the CpG island at 11q22-q23. We show that this region is completely demethylated in lymphocytes expressing ATM; however, no extensive hypermethylation was found in 9 T-PLL tumor DNA samples without evidence of ATM/p53 mutations. Because acute T-cell lymphoblastic leukemias (T-ALL) were also observed in ataxia-telangiectasia patients and T-ALL tumor cells contain chromosome 14 abnormalities, 19 presentation samples of T-ALL patients were analyzed for ATM mutations. Although T-ALL patients exhibited rare nucleotide substitutions not previously found in ATM, all were identified in the germ-line, indicating constitutional polymorphisms, potentially confined to ethnic subpopulations. The absence of somatic nucleotide changes in ATM in T-ALL as compared with T-PLL suggests a distinct pattern of genetic events in the development of the two leukemias.
authors.affiliation: Karolinska Institute, Department of Biosciences at NOVUM, Huddinge, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Luo
authors.forename: F M
authors.initials: FM
authors.lastname: Lu
authors.forename: S
authors.initials: S
authors.lastname: Hart
authors.forename: L
authors.initials: L
authors.lastname: Foroni
authors.forename: H
authors.initials: H
authors.lastname: Rabbani
authors.forename: L
authors.initials: L
authors.lastname: Hammarström
authors.forename: M R
authors.initials: MR
authors.lastname: Yuille
authors.forename: D
authors.initials: D
authors.lastname: Catovsky
authors.forename: A D
authors.initials: AD
authors.lastname: Webster
authors.forename: I
authors.initials: I
authors.lastname: Vorechovský
mesh_terms: D001260:Ataxia Telangiectasia / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D007446:Chromosome Inversion; D004247:DNA / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins; D006801:Humans; D015463:Leukemia, Prolymphocytic / Q000235:genetics*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics*; D019656:Loss of Heterozygosity; D009154:Mutation; D009687:Nuclear Proteins; D018807:Polymorphism, Single-Stranded Conformational; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000235:genetics*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C101693:NPAT protein, human; D009687:Nuclear Proteins; D011506:Proteins; D025521:Tumor Suppressor Proteins; D004247:DNA; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases