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)

T cell prolymphocytic leukaemia (T-PLL) is a chronic mature T cell malignancy with many random cytogenetic abnormalities. These imply that maintenance of genomic integrity is impaired. This is supported by the recent finding that the ataxia telangiectasia gene, ATM, which contributes to maintaining genomic integrity, is frequently mutated in this disease. To evaluate in T-PLL the role of other genes with comparable function, a fluorescence-based semi-automated assay was developed for BAT-25 and BAT-26. These markers contain sequences that are particularly unstable in cells with DNA mismatch repair defects. Application of the assay to 20 T-PLL cases found no evidence for such defects.
Leukemia 1999 Dec
PMID:Fluorescent BAT-25 and BAT-26 analysis of T cell prolymphocytic leukaemia. 1060 36

Chronic myeloid leukaemia (CML) is characterised by an indolent, chronic phase (CP) preceding an acute transformation to blast crisis (BC). While the BCR-ABL fusion oncogene is strongly implicated in the CP, the molecular changes underlying BC are largely unknown. The ataxia telangiectasia gene, ATM, is a candidate gene for this transformation because the complex karyotypes associated with BC of CML suggest that DNA double-strand break repair is defective and because the ABL pathway involves the interaction between the Abl and the Atm proteins. We performed a mutational analysis for ATM in CML using genomic DNA from 14 CML cell lines and 59 CML patients in BC. No clearly deleterious nucleotide changes were observed. A new polymorphism C4138T was discovered which results in a non-conservative amino acid substitution (H1380Y). This variant lies in the Atm recognition motif for the Abl protein. While ATM is unlikely to contribute substantially to CML, further investigation of the H1380Y substitution should clarify whether it has any functional effect.
Leukemia 2001 Sep
PMID:Investigation on the role of the ATM gene in chronic myeloid leukaemia. 1151 6

The genetic characterization of chronic lymphocytic leukemia (CLL) has made significant progress over the past few years. While conventional cytogenetic analyses only detected chromosome aberrations in 40-50% of cases, new molecular cytogenetic methods, such as fluorescence in situ hybridization (FISH), have greatly enhanced our ability to detect chromosomal abnormalities in CLL. Today, genomic aberrations are detected in over 80% of CLL cases. Genes potentially involved in the pathogenesis were identified with ATM in a subset of cases with 11q deletion and p53 in cases with 17p13 deletion. For the most frequent aberration, the deletion 13q14, candidate genes have been isolated. Genetic subgroups with distinct clinical features have been identified. 11q deletion is associated with marked lymphadenopathy and rapid disease progression. 17p deletion predicts for treatment failure with alkylating agents, as well as fludarabine and short survival times. In multivariate analysis 11q and 17p deletions provided independent prognostic information. Recently, another important issue of genetic risk classification in CLL was identified with the mutation status of the immunoglobulin variable heavy chain genes (V(H)). CLL cases with unmutated V(H) show more rapid disease progression and shorter survival times. Whether CD38 expression can serve as a surrogate marker for V(H) mutation status is currently discussed controversially. V(H) mutation status and genomic abnormalities, such as 17p and 11q deletion, have recently been shown to be related to each other, but were of independent prognostic information in multivariate analysis. Moreover, genomic aberrations and V(H) mutation status appear to give prognostic information irrespective of the clinical stage and may therefore allow a risk assessment for individual patients early in the course of their disease.
Leukemia 2002 Jun
PMID:Genetics of chronic lymphocytic leukemia: genomic aberrations and V(H) gene mutation status in pathogenesis and clinical course. 1204 Apr 31

It has been suggested that the expansion of the leukemic cells in chronic lymphocytic leukemia (CLL) is due to dysregulation of pathways of programmed cell death (apoptosis) rather than cell proliferation, although differences may exist in early vs late and treated vs untreated patients. In the present study, we analyzed the expression of 11 proteins in CLL cells that are implicated in the control of apoptosis, proliferation, and differentiation, and correlated this expression profile with survival. Using a quantitative solid-phase radioimmunoassay (RIA), we measured the cellular protein levels of Bcl-2, cyclin D1, PCNA, ATM, Fas, Bax, retinoic acid receptor alpha (RARalpha), retinoic acid receptor beta (RXRbeta), Flt1, VEGF, and cellular beta2-microglobulin in 230 samples of CLL. Univariate analysis using the Cox proportional hazard model showed a correlation with survival of only the following proteins: Bcl-2 (P < 0.001), cyclin D1 (P = 0.027), Fas (P = 0.055), PCNA (P < 0.001), and ATM (P = 0.028). In a multivariate analysis using classification and regression tree analysis (CART), five groups of patients (nodes) could be generated with significant differences of survival expectation (P < 0.0001) based on levels of expression of the above proteins. Based on CART analysis, Bcl-2 levels emerge as the most important protein in predicting survival between all 11 proteins studied. Patients with marked elevation in Bcl-2 levels had the worst outcome while patients with intermediate levels, but with high levels of PCNA and cyclin D1 or abnormal ATM expression had intermediate survival. These data indicate that intracellular levels of proteins such as Bcl-2, ATM, cyclin D1, and PCNA can be used as markers to predict clinical behavior and survival in patients with CLL. The pathways in which these proteins are involved may also represent possible targets for future therapeutic trials in CLL.
Leukemia 2002 Jun
PMID:Expression profile of 11 proteins and their prognostic significance in patients with chronic lymphocytic leukemia (CLL). 1204 Apr 36

Inherited biallelic mutations of the ATM (ataxia-telangiectasia mutated) gene cause ataxia-telangiectasia, a rare autosomal recessive disorder associated with a high incidence of childhood leukaemias and lymphomas, suggesting that ATM gene alterations may be involved in lymphomagenesis. Loss of heterozygosity at 11q22-23 (location of the ATM gene) is a frequent event in sporadic lymphoid tumours, and several studies have reported a high prevalence of ATM gene alterations in diverse sporadic lymphoproliferative disorders, adding evidence to the postulated contribution of ATM in the pathogenesis of these tumours. This mini-review will summarize the recently published data concerning the ATM gene in sporadic lymphoid malignancies and will discuss the apparent paradox between the predominance of nonsense mutations observed in patient with ataxia-telangiectasia and the high proportion of missense alterations found in sporadic lymphoid tumours.
Leukemia 2004 Feb
PMID:ATM gene and lymphoid malignancies. 1462 72

Expression of adenovirus E1A deregulates cell proliferation to facilitate viral DNA replication, prompting the initiation of apoptosis signaled primarily through proapoptotic BAK in productively infected cells. We demonstrate here that in uninfected cells, BAK is complexed with the anti-apoptotic BCL-2 family member Myeloid Cell Leukemia 1 (MCL-1). E1A expression during infection resulted in the specific down-regulation of MCL-1 through destabilization of the protein and loss of the mRNA. Upon loss of the MCL-1-BAK complex, BAK complexed with either BAX in proapoptotic E1B mutant adenovirus-infected cells, or with the adenovirus BCL-2 homolog E1B 19K in cells infected with the wild-type virus in which apoptosis is inhibited. Loss of MCL-1 was required to initiate the apoptotic pathway in infected cells as restoration of MCL-1 expression rescued infected cells from E1A-induced apoptosis. Analogous to E1A expression, DNA damage down-regulates MCL-1, and adenovirus infection resulted in the accumulation of phosphorylated H2AX and ataxia-telangiectasia mutant protein (ATM), hallmarks of DNA double-strand breaks. Thus, MCL-1 may function by maintaining BAK in an inactive state, and the loss of MCL-1 upon activation of the DNA damage response, perhaps through replication stress induced in virus infected cells, may be required to initiate the apoptotic response.
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PMID:DNA damage response and MCL-1 destruction initiate apoptosis in adenovirus-infected cells. 1463 75

In B-cell chronic lymphocytic leukemia (B-CLL), somatic mutation of IgVH genes defines a subgroup with favorable prognosis, whereas the absence of IgVH mutations is correlated with a worse outcome. Mutations of the BCL-6 gene are also observed in a subset of B-CLL, but the clinical significance of this molecular alteration remains uncertain. We examined the distribution of IgVH and BCL-6 gene mutations in 95 well-characterized patients with Binet stage A B-CLL, and correlated them with clinical, laboratory, cytogenetic findings and disease progression. Mutations of the BCL-6 gene were observed only in cases harboring mutated IgVH. Unexpectedly, coexistence of IgVH and BCL-6 mutations was correlated with shorter treatment-free interval (TFI) compared to cases harboring only IgVH mutation (median, 55 months vs not reached; P=0.01), resembling the clinical course of unmutated IgVH cases (median TFI, 44 months). As expected, deletions of 17p13 (P53 locus) and 11q22 (ATM locus) were observed in cases with unmutated IgVH, except one patient who showed mutations of both IgVH and BCL-6. No other statistically significant differences were observed among the genetic subgroups. Our data indicate that BCL-6 mutations identify a subgroup of Binet stage A B-CLL patients with a high risk of progression despite the presence of mutated IgVH gene.
Leukemia 2004 Apr
PMID:Bcl-6 mutation status provides clinically valuable information in early-stage B-cell chronic lymphocytic leukemia. 1496 Oct 33

CHK1: gene encodes for a serine/threonine kinase involved in the regulation of cell cycle progression and DNA damage checkpoints. To determine the role of CHK1 in the pathogenesis of lymphoid neoplasms and its relationship to other DNA damage response genes, we have analyzed the gene status, protein, and mRNA expression in a series of tumors and nonneoplastic lymphoid tissues. CHK1 protein and mRNA expression levels were very low in both reactive tissues and resting lymphoid cells, whereas tumor samples showed a variable pattern of expression related to their proliferative activity. However, seven aggressive tumors showed a dissociate pattern of extremely low or negative protein expression in spite of a high proliferative activity. Four of these tumors were diffuse large B-cell lymphomas (DLCLs) with concordant reduced levels of mRNA, whereas one blastoid mantle cell lymphoma (B-MCL) and two DLCLs had relatively normal levels of mRNA. No gene mutations, deletions, or hypermethylation of the promoter region were detected in any of these cases. In all these tumors ATM, CHK2, and p53 genes were wild type. These findings suggest that CHK1 inactivation in NHLs occurs by loss of protein expression in a subset of aggressive variants alternatively to ATM, CHK2, and p53 alterations.
Leukemia 2005 Jan
PMID:Checkpoint kinase 1 (CHK1) protein and mRNA expression is downregulated in aggressive variants of human lymphoid neoplasms. 1552 25

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.
Leukemia 2005 Aug
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

The T-lineage phenotype in children with acute lymphoblastic leukaemia (ALL) is associated with in vitro drug resistance and a higher relapse-risk compared to a precursor B phenotype. Our study was aimed to investigate whether mutations in the ATM gene occur in childhood T-lineage acute lymphoblastic leukaemia (T-ALL) that are linked to drug resistance and clinical outcome. In all, 20 different single nucleotide substitutions were found in 16 exons of ATM in 62/103 (60%) T-ALL children and 51/99 (52%, P = 0.21) controls. Besides the well-known polymorphism D1853N, five other alterations (S707P, F858L, P1054R, L1472W, Y1475C) in the coding part of ATM were found. These five coding alterations seem to occur more frequently in T-ALL (13%) than controls (5%, P = 0.06), but did not associate with altered expression levels of ATM or in vitro resistance to daunorubicin. However, T-ALL patients carrying these five coding alterations presented with a higher white blood cell count at diagnosis (P = 0.05) and show an increased relapse-risk (5-year probability of disease-free survival (pDFS) = 48%) compared to patients with other alterations or wild-type ATM (5-year pDFS = 76%, P = 0.05). The association between five coding ATM alterations in T-ALL, their germline presence, white blood cell count and unfavourable outcome may point to a role for ATM in the development of T-ALL in these children.
Leukemia 2005 Nov
PMID:Relation between genetic variants of the ataxia telangiectasia-mutated (ATM) gene, drug resistance, clinical outcome and predisposition to childhood T-lineage acute lymphoblastic leukaemia. 1640 93


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