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NCI CANCERLIT^® Search: Ataxia Telangiectasia - March 2002

Imprima English

National Cancer Institute^®
Ultima Vez Modificado: 1 de marzo del 2002

ATM function and telomere stability.

ATM: genome stability, neuronal development, and cancer cross paths.

A late onset variant of ataxia-telangiectasia with a compound heterozygous genotype, A8030G/7481insA.

No germline ATM mutation in a series of 16T-cell prolymphocytic leukemias.

TCL-1, MTCP-1 and TML-1 gene expression profile in non-leukemic clonal proliferations associated with ataxia-telangiectasia.

Radiosensitivity of ataxia telangiectasia and Nijmegen breakage syndrome homozygotes and heterozygotes as determined by three-color FISH

Table of Contents

1
UI - 11850786
AU - Pandita TK
TI - ATM function and telomere stability.
SO - Oncogene 2002 Jan 21;21(4):611-8
AD - Center for Radiological Research, College of Physicians and Surgeons, Columbia University, New York, New York, NY 10032, USA. tpl1@columbia.edu
Accumulation of DNA damage has been associated with the onset of senescence and predisposition to cancer. The gene responsible for ataxia telangiectasia (A-T) is ATM (ataxia-telangiectasia mutant), a master controller of cellular pathways and networks, orchestrating the responses to a specific type of DNA damage: the double strand break. Based on the homology of the human ATM gene to the TEL1, MEC1 and rad3 genes of yeast, it has now been demonstrated that mutations in ATM lead to defective telomere maintenance in mammalian cells. While ATM has both nuclear and cytoplasmic functions, this review will focus on its roles in telomere metabolism and how ATM and telomeres serve as controllers of cellular responses to DNA damage.

2
UI - 11665719
AU - Shiloh Y; Kastan MB
TI - ATM: genome stability, neuronal development, and cancer cross paths.
SO - Adv Cancer Res 2001;83():209-54
AD - Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Israel.
One of the cornerstones of the web of signaling pathways governing cellular life and differentiation is the DNA damage response. It spans a complex network of pathways, ranging from DNA repair to modulation of numerous processes in the cell. DNA double-strand breaks (DSBs), which are formed as a result of genotoxic stress or normal recombinational processes, are extremely lethal lesions that rapidly mobilize this intricate defense system. The master controller that pilots cellular responses to DSBs is the ATM protein kinase, which turns on this network by phosphorylating key players in its various branches. ATM is the protein product of the gene mutated in the human genetic disorder ataxia-telangiectasia (A-T), which is characterized by neuronal degeneration, immunodeficiency, sterility, genomic instability, cancer predisposition, and radiation sensitivity. The clinical and cellular phenotype of A-T attests to the numerous roles of ATM, on the one hand, and to the link between the DNA damage response and developmental processes on the other hand. Recent studies of this protein and its effectors, combined with a thorough investigation of animal models of A-T, have led to new insights into the mode of action of this master controller of the DNA damage response. The evidence that ATM is involved in signaling pathways other than those related to damage response, particularly ones relating to cellular growth and differentiation, reinforces the multifaceted nature of this protein, in which genome stability, developmental processes, and cancer cross paths.

3
UI - 11826028
AU - Saviozzi S; Saluto A; Taylor AM; Last JI; Trebini F; Paradiso MC; Grosso
TI - E; Funaro A; Ponzio G; Migone N; Brusco A A late onset variant of ataxia-telangiectasia with a compound heterozygous genotype, A8030G/7481insA.
SO - J Med Genet 2002 Jan;39(1):57-61

4
UI - 10939806
AU - Stoppa-Lyonnet D; Lauge A; Sigaux F; Stern MH
TI - No germline ATM mutation in a series of 16T-cell prolymphocytic leukemias.
SO - Blood 2000 Jul 1;96(1):374-6

5
UI - 11857346
AU - Chun HH; Castellvi-Bel S; Wang Z; Nagourney RA; Plaeger S;
TI - Becker-Catania SG; Naeim F; Sparkes RS; Gatti RA TCL-1, MTCP-1 and TML-1 gene expression profile in non-leukemic clonal proliferations associated with ataxia-telangiectasia.
SO - Int J Cancer 2002 Feb 20;97(6):726-31
AD - Department of Pathology, School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095-1732, USA.
We analyzed the role of 4 genes, TCL-1, MTCP-1, TML-1 and ATM, in the early pathogenesis of T cell leukemia, with particular interest in the characteristics of long-standing non-leukemic clonal proliferations in ataxia-telangiectasia (A-T) patients. Five patients were studied: 4 patients had A-T (2 of whom had non-leukemic clonal proliferations [ATCP]), 1 had B cell lymphoma and 1 had T-ALL; a fifth patient with T-PLL did not have A-T. We measured the levels of expression for TCL-1, MTCP-1 and TML-1. TCL-1, not expressed in unstimulated mature T cells, was upregulated in the peripheral blood leukocytes (PBL) of the 2 A-T patients with ATCP. It was also expressed in the malignant cells of the A-T patient with B cell lymphoma and the T-PLL cells of the patient without A-T. In the same cells, MTCP-1 type A was expressed equally in all 5 patients, as well as in the controls; MTCP-1 type B transcripts were not observed. TML-1, also not expressed in unstimulated T cells, was expressed in the PBL of one A-T patient with ATCP and in the leukemic cells of the non-A-T T-PLL patient. These expression patterns were compared to cellular immunophenotypes. The non-leukemic clonal T cell populations had the characteristics of immature T cells. We conclude that TCL-1 and TML-1 play a role in cell proliferation and survival but are not pivotal genes in the progression to malignancy, even when the ATM gene is mutated. Additional genetic alterations must occur to initiate tumorigenesis. Copyright 2001 Wiley-Liss, Inc.

6
UI - 11839094
AU - Neubauer S; Arutyunyan R; Stumm M; Dork T; Bendix R; Bremer M; Varon R;
TI - Sauer R; Gebhart E Radiosensitivity of ataxia telangiectasia and Nijmegen breakage syndrome homozygotes and heterozygotes as determined by three-color FISH chromosome painting.
SO - Radiat Res 2002 Mar;157(3):312-21
AD - Clinic of Radiotherapy, University Erlangen-Nurnberg, Germany.
A three-color chromosome painting technique was used to examine the spontaneous and radiation-induced chromosomal damage in peripheral lymphocytes and lymphoblastoid cells from 11 patients with ataxia telangiectasia (AT) and from 14 individuals heterozygous for an AT allele. In addition, cells from two homozygous and six obligate heterozygous carriers of mutations in the Nijmegen breakage syndrome gene (NBS) were investigated. The data were compared to those for chromosome damage in 10 unaffected control individuals and 48 cancer patients who had not yet received therapeutic treatment. Based on the well-documented radiation sensitivity of AT and NBS patients, it was of particular interest to determine whether the FISH painting technique used in these studies allowed the reliable detection of an increased sensitivity to in vitro irradiation of cells from heterozygous carriers. Peripheral blood lymphocytes and lymphoblastoid cells from both the homozygous AT and NBS patients showed the highest cytogenetic response, whereas the cells from control individuals had a low number of chromosomal aberrations. The response of cells from heterozygous carriers was intermediate and could be clearly differentiated from those of the other groups in double-coded studies. AT and NBS heterozygosity could be distinguished from other genotypes by the total number of breakpoints per cell and also by the number of the long-lived stable aberrations in both AT and NBS. Only AT heterozygosity could be distinguished by the fraction of unstable chromosome changes. The slightly but not significantly increased radiosensitivity that was found in cancer patients was apparently due to a higher trend toward rearrangements compared to the controls. Thus the three-color painting technique presented here proved to be well suited as a supplement to conventional cytogenetic techniques for the detection of heterozygous carriers of these diseases, and may be superior method.

The above citations and abstracts reflect those newly added to CANCERLIT for the month and topic listed in the title. The citations have been retrieved from CANCERLIT using a predefined search strategy of indexed subject terms. Although the search strategy has been refined as best as possible, citations may appear that are not directly related to the topic, and occasionally relevant references may be omitted.

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