title: Biallelic mutations in the ATM gene in T-prolymphocytic leukemia.
abstract: Ataxia-telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar ataxia, oculocutaneous telangiectasia, immune deficiency, genome instability and predisposition to malignancies, particularly T-cell neoplasms. The responsible gene, designated ataxia-telangiectasia mutated (ATM), was recently identified by positional cloning in the chromosomal region 11q22.3-23.1 (ref. 4, 5) ATM is 150 kb in length, consists of 66 exons and encodes a nuclear phosphoprotein of approximately 350 kDa (ref. 4-9). Although ATM is considered to be a tumorigenic factor in several human cancers, it has not yet been found mutated in tumors of non-AT patients. Given the marked predisposition of AT patients to develop neoplasms of the T-cell lineage, we analyzed a series of T-cell leukemias (T-prolymphocytic leukemia, or T-PLL) in non-AT patients in search of genomic changes associated with the development of this disease. Among the recurrent aberrations identified, deletion of the chromosome arm 11q was very frequent. Subsequent molecular cytogenetic analyses allowed us to define a small commonly deleted segment at 11q22.3-23.1 in 15 of 24 T-PLLs studied. Since this critical region contained ATM, we further analyzed the remaining copy of the gene in six cases showing deletions affecting one ATM allele. In all six cases, mutations of the second ATM allele were identified, leading to the absence, premature truncation or alteration of the ATM gene product. Thus, our study demonstrates disruption of both ATM alleles by deletion or point mutation in T-PLL, suggesting that ATM functions as a tumor-suppressor gene in tumors of non-AT individuals.
authors.affiliation: Medizinische Klinik und Poliklinik V, University of Heidelberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Stilgenbauer
authors.forename: C
authors.initials: C
authors.lastname: Schaffner
authors.forename: A
authors.initials: A
authors.lastname: Litterst
authors.forename: P
authors.initials: P
authors.lastname: Liebisch
authors.forename: S
authors.initials: S
authors.lastname: Gilad
authors.forename: A
authors.initials: A
authors.lastname: Bar-Shira
authors.forename: M R
authors.initials: MR
authors.lastname: James
authors.forename: P
authors.initials: P
authors.lastname: Lichter
authors.forename: H
authors.initials: H
authors.lastname: Döhner
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D002872:Chromosome Deletion; D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11; D017931:DNA Primers; D004268:DNA-Binding Proteins; D005819:Genetic Markers; D006801:Humans; D007621:Karyotyping; D016350:Leucine Zippers; D015463:Leukemia, Prolymphocytic / Q000235:genetics*; D015458:Leukemia, T-Cell / Q000235:genetics*; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000235:genetics; D017384:Sequence Deletion; D025521:Tumor Suppressor Proteins
chemical_list: D018797:Cell Cycle Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D005819:Genetic Markers; D011506:Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases