ATM mutations are associated with inactivation of theARF-TP53 tumor suppressor pathway in diffuse large B-cell lymphoma

Grønbæk, Kirsten; Worm, Jesper; Ralfkiær, Elisabeth; Ahrenkiel, Vibeke; Hokland, Peter; Guldberg, Per

doi:10.1182/blood-2002-02-0382

Cited by 77 publications

(53 citation statements)

References 46 publications

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“…S707P was found as a germline alteration in B-A4 and analysis of ATM locus failed to show any LOH. This alteration has been previously reported as mutation in early-onset breast cancer (Dork et al, 2001;Teraoka et al, 2001;Maillet et al, 2002) and in follicular lymphoma (Gronbaek et al, 2002). Unlike these studies, we found S707P with the same frequency in leukemic samples as in controls.…”

Section: Atm Alterations Of Probable Biological Significancecontrasting

confidence: 56%

“…Unlike these studies, we found S707P with the same frequency in leukemic samples as in controls. P1054R is a rare variant located in the ß-adaptin binding domain, often reported in breast cancer (Larson et al, 1997-98;Dork et al, 2001) and also described in lymphoid neoplasms (Stankovic et al, 1999;Gronbaek et al, 2002). F582L has already been reported in one T-ALL case (Luo et al, 1998) and found in B-C6 in association with a previously undescribed alteration (L1737F).…”

Section: Atm Alterations Of Probable Biological Significancementioning

confidence: 99%

“…In keeping with other cancer-predisposing genes, acquired mutations in the ATM gene have been described in sporadic neoplasia: truncating mutations or missense substitutions are frequently found in lymphoid malignancies such as B-cell chronic lymphocytic leukemia (B-CLL) (Bullrich et al, 1999;Stankovic et al, 1999;Pettitt et al, 2001;Stankovic et al, 2002), T-cell prolymphocytic leukemia (T-PLL) (Stilgenbauer et al, 1997;Vorechovsky et al, 1997;Stoppa-Lyonnet et al, 1998), mantle-cell lymphoma (MCL) (Schaffner et al, 2000;Camacho et al, 2002), and diffuse large B-cell lymphoma (Gronbaek et al, 2002). Since ATM inactivation is accompanied by a defective p53 response in B-CLL, and by increased chromosomal imbalances in MCL, it is thought to be involved in the early stages of lymphomagenesis by favoring the accumulation of additional chromosomal damages (Pettitt et al, 2001;Camacho et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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ATM gene alterations in childhood acute lymphoblastic leukemias

et al. 2003

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Hereditary ATM gene mutations cause ataxia-telangiectasia, a pleiotropic disorder associated with a high incidence of lymphoid malignancies. Acquired ATM alterations have been described in sporadic lymphoproliferative disorder suggesting that the ATM gene contributes to lymphomagenesis. To assess the prevalence of genomic ATM alterations in childhood acute lymphoblastic leukemias (ALL), we explored a series of 57 sporadic ALL cases (26 B-precursor ALL and 31 T-ALL) using DHPLC (Denaturing High-Performance Liquid Chromatography). We identified 28 distinct genomic ATM alterations in 14 patients (25%). Ten of them were scored as probably biologically significant and appear to be associated with a high risk of relapse ( P<0.01). Six alterations of potential biological significance were observed in 5 cases of B-precursor ALL (19%), while 5 were found in 3 cases of T-ALL (10%). In two cases of B-precursor ALL, the ATM alterations were found in the germline, indicating an ATM carrier status. We report here the high prevalence of genomic ATM alterations in childhood ALL. Our observations lend further support to the postulated contribution of ATM in lymphomagenesis.

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Section: Atm Alterations Of Probable Biological Significancecontrasting

confidence: 56%

Section: Atm Alterations Of Probable Biological Significancementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ATM gene alterations in childhood acute lymphoblastic leukemias

et al. 2003

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“…Inactivation of the p19 ARF -MDM2-p53 pathway accelerates lymphoma onset in Em-Myc mice (Eischen et al, 1999;Eischen et al, 2001a, b). While the p53 axis is rarely inactivated in human lymphoma, it is thought to be targeted as a late event in human MCL (Strasser et al, 1993;Gronbaek et al, 2002;Lai et al, 2002;Martinez et al, 2003). Inactivation of p53 predominantly occurs via point mutation of a single allele resulting in hyperaccumulation of dominant-negative p53 (Levine, 1997;Eischen et al, 1999).…”

Section: D1/t286a Lymphomas Exhibit Alterations In Prosurvival Pathwaysmentioning

confidence: 99%

Expression of constitutively nuclear cyclin D1 in murine lymphocytes induces B-cell lymphoma

et al. 2005

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Mantle cell lymphoma (MCL) is a B-cell lymphoma characterized by overexpression of cyclin D1 due to the t(11;14) chromosomal translocation. While expression of cyclin D1 correlates with MCL development, expression of wild-type (WT) cyclin D1 transgene in murine lymphocytes is unable to drive B-cell lymphoma. As cyclin D1 mutants that are refractory to nuclear export display heighten oncogenicity in vitro compared with WT D1, we generated mice expressing FLAG-D1/T286A, a constitutively nuclear mutant, under the control of the immunoglobulin enhancer, El. D1/T286A transgenic mice universally develop a mature B-cell lymphoma. Expression of D1/T286A in B lymphocytes results in S phase entry in resting lymphocytes and increased apoptosis in spleens of young premalignant mice. Lymphoma onset correlates with perturbations in p53/ MDM2/p19 Arf expression and with BcL-2 overexpression suggesting that alterations in one or both of these pathways may contribute to lymphoma development. Our results describe a cyclin D1-driven model of B-cell lymphomagenesis and provide evidence that nuclearretention of cyclin D1 is oncogenic in vivo.

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“…6 Methylation, thus, can serve as an alternative mechanism of gene inactivation during tumorigenesis. There is only one paper on methylation of ATM in lymphoma, 7 including FL but not MCL, and no methylation was identified. Here, we report on our studies to determine if hypermethylation of ATM contributes to lymphomagenesis by combining with upregulation of cyclin D1 in MCL, and BCL-2 in FL.…”

Section: To the Editormentioning

confidence: 99%

Absence of ATM hypermethylation in mantle cell and follicular lymphoma

et al. 2005

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patients are required to define the true efficacy of 153 Sm-EDTMP in eradicating MM, based on our experience, we believe that the agent should not be used as a substitute for TBI in preparative regimens in either autologous or allogeneic SCT. As such, we find the 'augmented' approach by Dispenzieri et al 1 very promising, and await with interest the results of their phase 2 trial. Mantle cell lymphoma (MCL) and follicular lymphoma (FL) are two forms of B-cell lymphoma derived from neoplastic transformation of their normal counterparts in the mantle zone and germinal center, respectively. 1 MCL is characterized in virtually all cases by t(11;14), with dysregulation of the cell cycle by upregulation of cyclin D1 located at 11q13. 1 On the other hand, FL is characterized by t(14;18) and upregulation of BCL-2 located at 18q21, which confers resistance to apoptosis on the malignant lymphoid cells. 1 ATM (A-T mutated) gene (localized to chromosome 11q22.3) encodes a cell cycle checkpoint-specific, serine-threonine kinase. In response to double-stranded DNA breaks (DSBs), ATM phosphorylates a panel of proteins including p53, Chk1, BRCA1 and Nbs1, resulting in cell cycle arrest and DNA repair, and is thus important in maintaining the integrity of the genome. This ensures passage of an intact genome in dividing cells, and elimination of cells carrying nonrepairable DSBs. 2 Mutation of ATM leads to ataxia telangiectasia, an autosomal recessive disorder, which is characterized by neurodegeneration, immunodeficiency and increased risk of cancer including lymphomas.In addition to the upregulation of cylin D1 associated with t(11;14) in MCL, a commonly deleted region at 11q22-q23 that encompasses the ATM locus has been identified in MCL. Subsequent mutation analysis of ATM, in 12 sporadic cases of MCL, showed a deletion of one ATM gene copy in seven, all of which harbored an inactivating point mutation in the remaining allele. In addition, biallelic ATM mutations were identified in two MCL patients without 11q deletions. 3 Using a microarray to screen lymphomas from 120 patients (including 28 MCL and 18 FL) for all possible ATM coding and splice junction mutations, ATM mutations were shown to be most frequent (12/28; 43%) in the mantle cell (MCL) subtype, but absent in FL. 4 In addition to deletion and mutation, methylation of gene promoter sites has now been identified as a frequently encountered mechanism of gene silencing in tumors. Indeed, ATM is frequently methylated in breast cancer. 5 Catalyzed by DNA methyltransferase, DNA methylation involves the addition of a methyl group to the carbon 5 position of the cytosine ring in the CpG dinucleotide, to form methylcytosine. 6 In many cancers, the CpG islands of selected genes are aberrantly methylated (hypermethylated), resulting in the repression of transcription of these genes. 6 Methylation, thus, can serve as an alternative Kaplan-Meier estimates of PFS, 153 Sm-EDTMP-based vs Cy-TBI preparative regimens.

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ATM mutations are associated with inactivation of theARF-TP53 tumor suppressor pathway in diffuse large B-cell lymphoma

Cited by 77 publications

References 46 publications

ATM gene alterations in childhood acute lymphoblastic leukemias

ATM gene alterations in childhood acute lymphoblastic leukemias

Expression of constitutively nuclear cyclin D1 in murine lymphocytes induces B-cell lymphoma

Absence of ATM hypermethylation in mantle cell and follicular lymphoma

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