Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A specific 14q32 breakpoint is observed in a homologous chromosome 14 translocation [t(14;14)q12q32] occurring in the T-cells of about 10% of patients with ataxia-telangiectasia (AT). To investigate whether the 14q32 breakpoint in AT occurs within the immunoglobulin gene cluster as is frequently detected in B-cell lymphoma, immunoglobulin clones were hybridized to Southern blots of DNA isolated from the T-cells of two AT patients with this chromosome 14 translocation. The 14q32 translocation breakpoints in these patients are apparently not within JH, S mu, C mu, S alpha-1 or -2, or C alpha-1 or -2, but one of the patients has an inverted duplication of at least 26 kilobases (kb) of the C mu region, with an associated 5' flanking deletion. The point of origin of the inverted duplication is within JH near the recombination signal for the J4 gene. This suggests that normal JH recombination mechanisms may have played a role in the development of this 14q32 chromosomal aberration. The presence of AT chromosomal breakpoints near other rearranging genes suggests a role for exaggerated recombination in the pathogenesis of chromosomal instability in AT.
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PMID:Inverted duplication of JH associated with chromosome 14 translocation and T-cell leukemia in ataxia-telangiectasia. 302 75

We report on 11 patients from 8 independent families (3 pairs of sibs) with a complex clinical pattern including microcephaly, peculiar "bird-like" face, growth retardation, and, in some cases, mild-to-moderate mental deficiency. Most of the patients have recurring respiratory tract infections. One girl has developed B-cell lymphoma. A detailed anthropometric study of 15 physical parameters, including 3 cephalic traits, was performed. It was possible to study the chromosomes of PHA-stimulated lymphocytes in all of the patients. We found structural aberrations with multiple rearrangements, preferentially involving chromosomes 7 and 14 in a proportion of metaphases in all individuals. Profound humoral and cellular immune defects were observed. Serum AFP levels were within normal range. Radioresistant DNA synthesis was strongly increased in all 8 patients who were hitherto studied in this respect. Our patients fulfill the criteria of the Nijmegen breakage syndrome, which belongs to the growing category of ataxia telangiectasia-related genetic disorders. In light of the increased predisposition to malignancy in this syndrome, an accurate diagnosis is important for the patient.
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PMID:Eleven Polish patients with microcephaly, immunodeficiency, and chromosomal instability: the Nijmegen breakage syndrome. 754 70

Ataxia telangiectasia (A-T) is a rare autosomal recessive disorder characterized by cerebellar ataxia, oculocutaneous telangiectasia, and variable degrees of humoral and cellular immunodeficiency. Affected individuals are known to exhibit a high incidence of lymphoma and leukemia. Because of increased chemosensitivity, the treatment of A-T patients with malignancies requires extremely careful planning and caution with respect to the use of chemotherapy. The authors report on a 12-year-old boy with A-T who developed B-cell lymphoma. He received a half-dose of the drugs administered according to the acute lymphoblastic leukemia (ALL) protocol issued by our children's cancer study group (9104 Standard Risk Protocol, Tokai Pediatric Oncology Study Group). As a result, he continues to be in complete remission and free of treatment complications 32 months after the diagnosis of B-cell lymphoma.
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PMID:Ataxia telangiectasia associated with B-cell lymphoma: the effect of a half-dose of the drugs administered according to the acute lymphoblastic leukemia standard risk protocol. 978 9

Mantle cell lymphoma (MCL), described almost 3 decades ago as centrocytic lymphoma and by a variety of other names, was initially recognized morphologically. MCL is a classic illustration of how the field of hematopathology and our basic understanding of neoplasia have evolved. The advent of immunophenotypic and increasingly sophisticated genotypic and cytogenetic studies, together with clinical investigations, have led to a better practical and biologic understanding of MCL and have broader implications as well. MCL is now recognized as an aggressive, difficult to treat, B-cell lymphoma with a broader morphologic spectrum than was initially appreciated and a characteristic phenotype (CD5+, CD10-, CD23-, FMC7+). Virtually all MCLs carry the translocation t(11;14)(q13;q32) with overexpression of the involved CCND1 (cyclin D1) gene. Additional cytogenetic and molecular abnormalities have been identified, including some that are early events (such as ATM gene deletion and mutation) and others that appear to be late events (such as deletions and mutations in the negative cell cycle regulatory elements p53, p16, and p18). The latter are often associated with a blastoid morphology and more aggressive clinical course. Ongoing clinical and basic investigations including microarray analysis will undoubtedly provide additional insights into MCL and perhaps more effective and specific therapeutic modalities.
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PMID:From centrocytic to mantle cell lymphoma: a clinicopathologic and molecular review of 3 decades. 1182 69

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.
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PMID:TCL-1, MTCP-1 and TML-1 gene expression profile in non-leukemic clonal proliferations associated with ataxia-telangiectasia. 1185 46

The ATM serine-threonine kinase plays a central role in the cellular response to DNA damage. Germ-line mutations in the ATM gene cause ataxia-telangiectasia (A-T), a multisystem disorder associated with predisposition to lymphoma and acute leukemia. Moreover, somatic ATM mutations have been identified in T-cell prolymphocytic leukemia, mantle cell lymphoma, and B-cell chronic lymphocytic leukemia. In this study, the entire ATM coding sequence was examined in genomic DNA from 120 lymphoid neoplasms. Novel mutations and mutations implicated in cancer and/or A-T were found in 9 of 45 diffuse large B-cell lymphomas (DLBCLs), 2 of 24 follicular lymphomas, and 1 of 27 adult acute lymphoblastic leukemias, whereas no such mutations were detected among 24 peripheral T-cell lymphomas. The mutational spectrum consisted of 2 nonsense mutations, 1 mutation affecting RNA splicing, and 10 missense variants. Most of these mutations were associated with loss or mutation of the paired ATM allele, consistent with biallelic inactivation of ATM. Of the 9 DLBCLs with ATM mutations, 7 also carried TP53 mutations and/or deletions of the INK4a/ARF locus (P =.003). The ATM 735C>T substitution previously considered a rare normal variant was found to be 5.6 times more frequent in individuals with DLBCL than in random individuals (P =.026), suggesting that it may predispose to B-cell lymphoma. Our data suggest that ATM mutations contribute to the development of DLBCL, and that ATM and the ARF-p53 tumor suppressor pathway may cooperate in the pathogenesis of this malignancy.
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PMID:ATM mutations are associated with inactivation of the ARF-TP53 tumor suppressor pathway in diffuse large B-cell lymphoma. 1214 28

We present the study of 16 cases of splenic marginal zone B-cell lymphoma (SMZBL) combining conventional cytogenetics and fluorescence in situ hybridization technique (FISH). We used a locus specific probe (11q22.3) that hybridizes with Ataxia Telangiectasia Mutated gene (ATM) and a centromeric probe of chromosome 11 as a control. Deletions in ATM gene region have been found in B-cell chronic lymphocytic leukemia (B-CLL) and mantle cell lymphoma (MCL) and have been considered as an independent prognosis factor in these pathologies. The aim of our study was to determine the ATM status in SMZBL because no specific studies concerning ATM status in SMZBL have been reported and other B-cell malignances have shown ATM deletions. No deletions were detected in any of the 16 cases. ATM deletions could be considered a rare event in SMZBCL.
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PMID:Absence of ATM deletions in 16 cases of splenic marginal-zone B-cell lymphoma (SMZBCL). 1460 69

Clonally related composite lymphomas of Hodgkin's lymphoma (HL) and Non-Hodgkin's lymphoma (NHL) represent models to study the multistep transformation process in tumorigenesis and the development of two distinct tumors from a shared precursor. We analyzed six such lymphomas for transforming events. The HLs were combined in two cases with follicular lymphoma (FL), and in one case each with B-cell chronic lymphocytic leukemia, splenic marginal zone lymphoma, mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL). In the HL/FL and HL/MCL combinations, BCL2/IGH and CCND1/IGH translocations, respectively, were detected in both the HL and NHL. No mutations were found in the tumor suppressor genes FAS, NFKBIA and ATM. The HL/DLBCL case harbored clonal replacement mutations of the TP53 gene on both alleles exclusively in the DLBCL. In conclusion, we present the first examples of molecularly verified IgH-associated translocations in HL, which also show that BCL2/IGH or CCND1/IGH translocations can represent early steps in the pathogenesis of composite HL/FL or HL/MCL. The restriction of the TP53 mutations to the DLBCL in the HL/DLBCL case exemplifies a late transforming event that presumably happened in the germinal center and affected the fate of a common lymphoma precursor cell towards development of a DLBCL.
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PMID:Insights into the multistep transformation process of lymphomas: IgH-associated translocations and tumor suppressor gene mutations in clonally related composite Hodgkin's and non-Hodgkin's lymphomas. 1597 55

Aberrant hypermethylation of CpG islands in the promoter region of tumor suppressor and other important genes in neoplastic cells of lymphoma has been demonstrated to be one of the mechanisms for epigenetic loss of gene function. In this study, we analyzed promoter hypermethylation of the following genes in 49 cases of primary gastric lymphoma (PGL): ATM, p16INK4a(CDKN2A), hMLH1, MGMT, DAPK, and CDH1(ECAD). The PGL cases studied included 26 (53%) cases of diffuse large B-cell lymphoma (DLBCL), 12 (25%) cases of extranodal marginal zone lymphoma (MZL), 7 (14%) cases of MZL with large cell transformation (MZL/DLBCL), 1 (2%) case of follicular lymphoma (FL), one (2%) case of Burkitt-like lymphoma (BL), one case (2%) of lymphoplasmacytic lymphoma (LPL) and one case (2%) of peripheral T-cell lymphoma. Available pathologic data regarding to extragastric involvement at the time of resection of the PGLs were reviewed and correlated. Promoter hypermethylation was detected in 6 of 49 (12.2%) cases for ATM; 13 of 49 (26.5%) for p16INK4a, 19 of 49 (38.8%) for hMLH1; 22 of 49 (44.9%) for MGMT; 27 of 49 (55.1%) for DAPK and 16 of 49 (32.7%) for CDH1. A total of 85% of the PGLs had promoter hypermethylation in at least one of these genes. With different histologic subtypes, promoter hypermethylation of DAPK, hMLH1, and CDH1 genes occurred in 70%, 42%, and 42% respectively for DLBCL, which appeared to be higher than combined MZL and MZL/DLBCL subgroup. Approximately 81% PGLs demonstrated H. pylori infection by immunohistochemistry. H. pylori status did not appear to be statistically correlated with promoter hypermethylation of the genes. Of 37 PGL cases, 19 cases had extragastric involvement at the time of resection, indicating relatively higher stage disease. The frequencies of promoter methylation in those cases were 58% for DAPK, 42% for hMLH1, 37% for CDH1, 26% for p16INK4a and 11% for ATM respectively. The promoter methylation at MGMT gene was significantly higher in the PGLs without extragastric involvement (61%) as compared to those with extragastric involvement (26%).
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PMID:Promoter hypermethylation of multiple genes in gastric lymphoma. 1785 7

Children with primary immunodeficiency or chromosomal breakage syndromes are at increased risk of developing non-Hodgkin lymphomas; they cannot tolerate standard chemotherapy regimens. We report two children with diffuse, large, B-cell lymphoma; one had ataxia telangiectasia and one had common variable immunodeficiency. Both were given rituximab, 1 as monotherapy and 1 in combination with a reduced CHOP regimen. Complete remission was obtained in each patient. Use of rituximab as a first-line monotherapy or in conjunction with reduced chemotherapy should be considered to reduce cytotoxic effects.
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PMID:Rituximab as monotherapy and in addition to reduced CHOP in children with primary immunodeficiency and non-Hodgkin lymphoma. 1914 90


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