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 panel of fluorescence in situ hybridisation (FISH) probes was used on 894 cases to target chromosome 11q, 13q, 17p deletions (del), trisomy 12 (+12) in all and 6q deletion in 59. Chronic lymphocytic leukaemia (CLL) immunophenotype (CD5 and CD19 with CD23) was found in 509 cases (average age 67.7 years, 319 males and 190 females). Among the 509 CLL cases 349 (68.6%) had FISH (4-probe panel) abnormalities: 160 del 13q [45.8% (122-del 13q, 18-biallelic del 13q, 20-monoallelic/biallelic del 13q)], 71 tri 12 (20.3%), 17 del ATM (5%), 12 del p53 (3.4%) and 89 > or = 2 FISH abnormalities (25.5%). Of 151/509 cases karyotyped, 108 were normal and 43 (43/151 = 28.5%) abnormal. Del 6q was found in 1/59 (1.6%) FISH cases and in 6/151 (4%) karyotypes. In 14 CD23 negative cases IGH/BCL1 FISH detected t(11;14) and was confirmed to be mantle cell lymphoma. Multiple probes/panels that included IGH probe were ordered for 57 CLL cases, 11 had an IGH rearrangement with an unidentified partner. This study favours the inclusion of del 6q and IGH probes in the CLL panel. The FISH panel could also serve to monitor 13q deletion for secondary changes with adverse prognosis. Understanding prognosis in specific types of 13q deletion would enhance outcome prediction.
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PMID:Chronic lymphocytic leukaemia profiled for prognosis using a fluorescence in situ hybridisation panel. 1648 71

Mantle Cell Lymphoma (MCL) is a well-known histological and clinical subtype of B-cell non-Hodgkin's Lymphomas. It is usually characterized by an aggressive disease course, presenting with advanced stage disease at diagnosis and with low response rates to therapy. However few cases of indolent course MCL have been described. We herein report a case of MCL with splenomegaly and peripheral blood involvement as main clinical features. The patient underwent moderate dose splenic radiation therapy and achieved spleen downsizing and peripheral blood complete remission. Splenic irradiation has been extensively used in the past as palliative treatment in several lymphoproliferative disorders and a systemic effect and sometimes peripheral blood complete remissions have been observed. Mainly advocated mechanisms responsible for this phenomenon are considered direct radiation-induced apoptotic cell death, immune modulation via proportional changes of lymphocyte subsets due to known differences in intrinsic radiosensitivity and a radiation-induced cytokine release. The peculiar intrinsic radiosensitivity pattern of lymphoid cells could probably be explained by well-defined individual genetic and molecular features. In this context, among NHLs, MCL subtype has the highest rate of ATM (Ataxia Teleangiectasia Mutated) inactivation. While the ATM gene is thought to play a key-role in detecting radiation-induced DNA damage (especially Double Strand Breaks), recent in vitro data support the hypothesis that ATM loss may actually contribute to the radiosensitivity of MCL cells. ATM status was retrospectively investigated in our patient, with the tool of Fluorescence In Situ Hybridization, showing a complete inactivation of a single ATM allele secondary to the deletion of chromosomal region 11q22-23. The presence of this kind of cytogenetic aberration may be regarded in the future as a potential predictive marker of radiation response.
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PMID:Peripheral blood complete remission after splenic irradiation in mantle-cell lymphoma with 11q22-23 deletion and ATM inactivation. 1695 11

Mantle cell lymphoma is a clinically heterogeneous disease, where further elucidation of pathogenetic mechanisms and better prognostic information is required. We evaluated genetic aberrations by interphase FISH on tissue sections or cytological material in 38 samples from 30 MCL patients, including 5 cases with cyclin D1 3'UTR low, which previously has been associated to unfavourable prognosis. The findings have been related to proliferation and clinical outcome. All but one of MCL showed t(11:14) translocation and in 22/30 samples taken at diagnosis or first relapse, one or several cytogenetic changes were detected; 11 deletions of ATM, 13 p53 deletions, 8 numerical c-myc-aberrations and 6 delp16. All but one MCL with low cyclin D1 3'UTR had additional cytogenetic changes, however no particular genetic change was strictly associated with this MCL variant. One fourth of MCL had none of the investigated additional aberrations and these tumours were in general less proliferative and some of these patients had a very long survival.
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PMID:Characterization of genetic changes in MCL by interphase FISH on tissue sections. 1778 2

Mantle cell lymphoma (MCL) is a well-defined lymphoid neoplasm characterized by a proliferation of mature B lymphocytes expressing CD5 that may show a spectrum of morphological and phenotypic features broader than initially described. Although some patients may follow an indolent clinical evolution, in most of them the tumour has an aggressive behaviour with poor response to conventional chemotherapy. The genetic hallmark is the t(11;14)(q13;q32) translocation leading to the overexpression of cyclin D1, which is considered the initial oncogenic event. In addition to this translocation, MCL may carry a high number of secondary chromosomal and molecular alterations that target regulatory elements of the cell cycle machinery and senescence (BMI1/INK4/ARF/CDK4/RB1), DNA damage response pathways (ATM/CHK2/p53), and cell survival signals. The knowledge of these mechanisms and their influence on the behaviour of the tumour are facilitating the development of prognostic models with a more precise prediction of the clinical evolution of the patients. This information coupled with the availability of a new generation of innovative drugs targeting basic molecular process of the tumour cells, should facilitate the design of new therapeutic protocols able to overcome the resistance of this aggressive lymphoma to conventional treatments and improve the life expectancy of the patients.
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PMID:Advances in the understanding of mantle cell lymphoma. 1841 Apr 53

Mantle cell lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation and several other cytogenetic aberrations, including heterozygous loss of chromosomal arms 1p, 6q, 11q and 13q and/or gains of 3q and 8q. The common intervals of chromosomal imbalance have been narrowed down using array-comparative genomic hybridization (CGH). However, the chromosomal intervals still contain many genes potentially involved in MCL pathogeny. Combined analysis of tiling-resolution array-CGH with gene expression profiling on 11 MCL tumours enabled the identification of genomic alterations and their corresponding gene expression profiles. Only subsets of genes located within given cytogenetic anomaly-intervals showed a concomitant change in mRNA expression level. The genes that showed consistent correlation between DNA copy number and RNA expression levels are likely to be important in MCL pathology. Besides several 'anonymous genes', we also identified various fully annotated genes, whose gene products are involved in cyclic adenosine monophosphate-regulated pathways (PRKACB), DNA damage repair, maintenance of chromosome stability and prevention of rereplication (ATM, ERCC5, FBXO5), energy metabolism (such as genes that are involved in the synthesis of proteins encoded by the mitochondrial genome) and signal transduction (ARHGAP29). Deregulation of these gene products may interfere with the signalling pathways that are involved in MCL tumour development and maintenance.
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PMID:Integrated genomic and expression profiling in mantle cell lymphoma: identification of gene-dosage regulated candidate genes. 1869 51

Mantle cell lymphoma (MCL) is genetically characterized by 11q13 translocations leading to the overexpression of CCND1, and additional secondary genomic alterations that may be important in the progression of this disease. We have analyzed 22 MCL cases and 10 MCL cell lines using multicolor fluorescence in situ hybridization (M-FISH), FISH, and comparative genomic hybridization (CGH). The 19 cases with abnormal karyotype showed the t(11;14)(q13;q32) translocation and, additionally, 89% of cases showed both numerical (n = 58) and structural (n = 77) aberrations. All but one MCL cell line showed t(11;14) and structural and numerical alterations in highly complex karyotypes. Besides 11 and 14, the most commonly rearranged chromosomes were 1, 8, and 10 in the tumors and 1, 8, and 9 in the cell lines. No recurrent translocations other than the t(11;14) were identified. However, we identified 17 recurrent breakpoints, the most frequent being 1p22 and 8p11, each observed in four cases and two cell lines. Interestingly, five tumors and four cell lines displayed a complex t(11;14), cryptic in one case and two cell lines, preferentially involving chromosome 8. In typical MCL, ATM gene deletions were significantly associated with a high number of structural and numerical alterations. In conclusion, MCL does not have recurrent translocations other than t(11;14), but shows recurrent chromosomal breakpoints. Furthermore, most MCL harbor complex karyotypes with a high number of both structural and numerical alterations affecting several common breakpoints, leading to various balanced and unbalanced translocations.
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PMID:Multiple recurrent chromosomal breakpoints in mantle cell lymphoma revealed by a combination of molecular cytogenetic techniques. 1870 64

The t(11;14)(q13;q32) is the hallmark of mantle cell lymphoma (MCL). Additional genetic alterations occur in the majority of cases. This study aimed to design a polymerase chain reaction (PCR) assay to determine the incidence and relevance of recurrent gene copy number aberrations in this disease. Forty-two MCL cases with frozen- or paraffin-embedded (FFPE) tissues were selected. Three different quantitative Multiplex PCR of Short Fluorescent Fragments (QMPSF) assays were designed to simultaneously analyse eight genes (CDKN2A, RB1, ATM, CDK2, TP53, MYC, CDKN1B, MDM2), to analyse the 9p21 locus (CDKN2A/CDKN2B) and FFPE tissues. Gains of MYC, CDK2, CDKN1B, and MDM2 were observed in 10% of cases. Losses of RB1, CDKN2A, ATM or TP53 were observed in 38%, 31%, 24% and 10% of cases, respectively. Analysis of the 9p21 locus indicated that, in most cases, tumours displayed a complete inactivation of p14(ARF)/p15I(NK4B)/p16I(NK4A). CDKN2A and MYC aberrations were associated with a high MCL international prognostic index (MIPI). CDK2/MDM2 gains and CDKN2A/TP53 losses correlated with an unfavourable outcome. PCR experiments with frozen and FFPE-tissues indicated that our approach is valid in a routine diagnostic setting, providing a powerful tool that could be used for patient stratification in combination with MIPI in future clinical trials.
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PMID:Detection of gene copy number aberrations in mantle cell lymphoma by a single quantitative multiplex PCR assay: clinicopathological relevance and prognosis value. 1959 47

The Ataxia Telangiectasia Mutated (ATM) gene is frequently inactivated in lymphoid malignancies such as chronic lymphocytic leukemia (CLL), T-prolymphocytic leukemia (T-PLL), and mantle cell lymphoma (MCL) and is associated with defective apoptosis in response to alkylating agents and purine analogues. ATM mutant cells exhibit impaired DNA double strand break repair. Poly (ADP-ribose) polymerase (PARP) inhibition that imposes the requirement for DNA double strand break repair should selectively sensitize ATM-deficient tumor cells to killing. We investigated in vitro sensitivity to the poly (ADP-ribose) polymerase inhibitor olaparib (AZD2281) of 5 ATM mutant lymphoblastoid cell lines (LCL), an ATM mutant MCL cell line, an ATM knockdown PGA CLL cell line, and 9 ATM-deficient primary CLLs induced to cycle and observed differential killing compared with ATM wildtype counterparts. Pharmacologic inhibition of ATM and ATM knockdown confirmed the effect was ATM-dependent and mediated through mitotic catastrophe independently of apoptosis. A nonobese diabetic/severe combined immunodeficient (NOD/SCID) murine xenograft model of an ATM mutant MCL cell line demonstrated significantly reduced tumor load and an increased survival of animals after olaparib treatment in vivo. Addition of olaparib sensitized ATM null tumor cells to DNA-damaging agents. We suggest that olaparib would be an appropriate agent for treating refractory ATM mutant lymphoid tumors.
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PMID:The PARP inhibitor olaparib induces significant killing of ATM-deficient lymphoid tumor cells in vitro and in vivo. 2073 57

Mantle cell lymphoma (MCL), an aggressive subtype of non-Hodgkin lymphoma, is characterized by the hallmark translocation t(11;14)(q13;q32) and the resulting overexpression of cyclin D1 (CCND1). Our current knowledge of this disease encompasses frequent secondary cytogenetic aberrations and the recurrent mutation of a handful of genes, such as TP53, ATM, and CCND1. However, these findings insufficiently explain the biologic underpinnings of MCL. Here, we performed whole transcriptome sequencing on a discovery cohort of 18 primary tissue MCL samples and 2 cell lines. We found recurrent mutations in NOTCH1, a finding that we confirmed in an extension cohort of 108 clinical samples and 8 cell lines. In total, 12% of clinical samples and 20% of cell lines harbored somatic NOTCH1 coding sequence mutations that clustered in the PEST domain and predominantly consisted of truncating mutations or small frame-shifting indels. NOTCH1 mutations were associated with poor overall survival (P = .003). Furthermore, we showed that inhibition of the NOTCH pathway reduced proliferation and induced apoptosis in 2 MCL cell lines. In summary, we have identified recurrent NOTCH1 mutations that provide the preclinical rationale for therapeutic inhibition of the NOTCH pathway in a subset of patients with MCL.
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PMID:Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma. 2238 87

We have recently reported the application of RNAseq to mantle cell lymphoma (MCL) transcriptomes revealing recurrent mutations in NOTCH1. Here we describe the targeted resequencing of 18 genes mutated in this discovery cohort using a larger cohort of MCL tumors. In addition to frequent mutations in ATM, CCND1, TP53, and NOTCH1, mutations were also observed recurrently in MEF2B, TRAF2, and TET2. Interestingly, the third most frequently mutated gene was UBR5, a gene encoding a 2799aa protein, with multiple functions, including E3 ligase activity based on a conserved cysteine residue at the C-terminus. Nonsynonymous mutations were detected in 18% (18/102) of tumors, with 61% of the mutations resulting in frameshifts in, or around, exon 58, predicted to result in the loss of this conserved cysteine residue. The recurrence and clustering of deleterious mutations implicate UBR5 mutations as a critical pathogenic event in a subgroup of MCL.
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PMID:The E3 ubiquitin ligase UBR5 is recurrently mutated in mantle cell lymphoma. 2340 52


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