Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:5.99.1.3 (topoisomerase)
9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) in infants have in common a high incidence of translocations of the MLL gene at chromosome band 11q23. Similar translocations occur in leukemias associated with chemotherapies that target DNA topoisomerase II. MLL has numerous different partner genes. The role of the many MLL fusion proteins in leukemogenesis is not yet understood. The t(4;11) translocation, the most common translocation in infant ALL, adversely affects the outcome. Additional genetic changes, especially Ikaros alterations, are found in infant ALL. Other forms of myeloid leukemia in infants present as myelodysplastic and myeloproliferative syndromes, which may be associated with constitutional disorders. This review will consider all leukemia in infants, but will focus on leukemias with MLL gene translocations.
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PMID:Leukemia in infants. 1039 90

TEL-AML1 gene fusion derived by chromosomal translocation is a common acquired genetic lesion in pediatric cancer that is present in approximately 25% of B-cell precursor acute lymphoblastic leukemias, and recent evidence suggests that this recombination event may initiate leukemogenesis prenatally during fetal hemopoiesis. Analysis of the DNA sequence and structure surrounding the breakpoints may reveal clues to their formation. A long-distance inverse PCR strategy was used to amplify TEL-AML1 genomic fusion sequences from diagnostic DNA from nine patients. Breakpoints were scattered within the 14 kb of intronic DNA between exons 5 and 6 of TEL and in two putative cluster regions within AML1 intron 1. Fusion sequences exhibited characteristic signs of nonhomologous end joining, including microhomologies at the end points, and small deletions and duplications. DNA sequences near the breakpoints did not reveal any consistent characteristic signal sequences of the V(D)J recombinase, topoisomerase II consensus sites, or other sequence motifs associated with recombination. However, several translocations occurred near a repeat region of TEL that was found to be highly polymorphic. This region was cloned and found in nuclease sensitivity assays to exhibit paranemic structures, which may have contributed to DNA breakage or illegitimate recombination. The data are compatible with the possibility that TEL-AML1 translocations occur by nonhomologous recombination involving imprecise, constitutive repair processes following DNA double-strand breaks.
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PMID:Structure and possible mechanisms of TEL-AML1 gene fusions in childhood acute lymphoblastic leukemia. 1046 10

The frequency of leukemia and myelodysplasia following treatment with cytotoxic agents is increasing. Theses treatment-related leukemias raise both theoretical and practical concerns. On a theoretical basis, cytogenetic and molecular abnormalities described constitute useful models to study leukemogenesis. On a practical basis, prognosis of treatment related-leukemia is somehow unfavorable and implies to take in account this risk in the development of combination therapy for solid tumors or hematological malignancies. There are two distinctive types of treatment-induced leukemia: those secondary after alkylating agents and those secondary after topoisomerase-II- inhibitors. These two types of leukemia after regarding their clinical and their hematological characteristics, but also regarding their prognosis and their associated molecular abnormalities. Leukemias induced by alkylating agents occur generally 5 or 6 years after the beginning of the chemotherapy and are preceded by a more or less long phase of pancytopenia or myelodysplasia and according to their cytologic aspects are difficult to be classified within FAB classification. Their prognosis is pejorative. The most commonly found cytogenetic abnormalities associated with these types of induced leukemia are losses or deletions of chromosomes 5 and 7. Leukemias induced by topoisomerase-II-inhibitors occur shortly after the treatment (12 to 30 months), they begin generally suddenly without preleukemia prodom and their more frequent cytological aspects are M4 and M5 type. The prognosis is less severe than alkylating agent related forms with higher response rates and is dependant of discovered cytogenetic abnormalities. The more frequent molecular abnormalities are not chromosome deletions but balanced translocations. They affect particularly the MLL gene located at band 11q23. Other translocations have been described in this type of leukemia and are comparable to the one found in the de novo leukemia (t8;21, t15;17) for example. The evaluation of the risk of treatment-related leukemia for a given chemotherapeutic agent is difficult as for as current treatment use the combination of several agents potentially leukemogenic (chemotherapy and radiotherapy, combination chemotherapy). It is necessary to set up an up-dated data register in order to centralize all therapy-related myelodysplasia and leukemia within the treatment of a given type of cancer.
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PMID:[Leukemias induced by anticancer chemotherapies]. 1058 9

We describe a boy with Fanconi anemia (FA) who developed acute lymphoblastic leukemia (ALL) (FAB-LI) followed by acute myeloid leukemia (AML) (FAB-M5) at relapse. The patient was diagnosed with early pre-B-cell ALL without preceding aplastic anemia and was treated with ALL-oriented chemotherapy which included doxorubicin (a total dose of 140 mg/m(2) administered), which is a topoisomerase II inhibitor. Complete remission was obtained, but after 38 weeks AML developed. The karyotype of ALL cells at diagnosis showed 46,XY, and that of AML cells at relapse was 46,XY, t(11;16)(q23;p13). An MLL gene rearrangement and MLL-CBP chimeric mRNA were found in AML, but not in ALL. A diagnosis of FA was confirmed by an increased number of chromosomal breaks and rearrangements in peripheral blood lymphocytes cultured with mitogen in the presence of mitomycin C. We conclude that this FA patient developed ALL followed by a therapy-related t(11;16)-AML resulting in an MLL-CBP fusion. Further examination of such patients would shed light on leukemogenesis in FA patients. Genes Chromosomes Cancer 27:264-269, 2000.
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PMID:MLL-CBP fusion transcript in a therapy-related acute myeloid leukemia with the t(11;16)(q23;p13) which developed in an acute lymphoblastic leukemia patient with Fanconi anemia. 1067 15

Thiopurines and topoisomerase II-targeted drugs (e.g., etoposide) are widely used anticancer drugs. However, topoisomerase II-targeted drugs can cause acute myeloid leukemia, with the risk of this secondary leukemia linked to a genetic defect in thiopurine catabolism. Chronic thiopurines result in thioguanine substitution in DNA. The effect of these substitutions on DNA topoisomerase II activity is not known. Our goal was to determine whether deoxythioguanosine substitution alters DNA cleavage stabilized by human topoisomerase II. We studied four variations of a 40 mer oligonucleotide with a topoisomerase II cleavage site, each with a single deoxythioguanosine in a different position relative to the cleavage site (-1 or +2 in the top and +2 or +4 in the bottom strand). Deoxythioguanosine substitution caused position-dependent quantitative effects on cleavage. With the -1 or +2 top and +2 or +4 bottom substitutions, mean topoisomerase II-induced cleavage was 0.6-, 2.0-, 1.1-, and 3.3-fold that with the wild-type substrate (P=0. 011, < 0.008, 0.51, and < 0.001, respectively). In the presence of 100 microM etoposide, cleavage was enhanced for wild-type and all thioguanosine-modified substrates relative to no etoposide, with the +4 bottom substitution showing greater etoposide-induced cleavage than the wild-type substrate (P=0.015). We conclude that thioguanine incorporation alters the DNA cleavage induced by topoisomerase II in the presence and absence of etoposide, providing new insights to the mechanism of thiopurine effect and on the leukemogenesis of thiopurines, with or without topoisomerase inhibitors.
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PMID:Thioguanine substitution alters DNA cleavage mediated by topoisomerase II. 1105 56

In order to identify genomic changes associated with an etoposide resistance acquisition, we used comparative genomic hybridization (CGH) to compare a human lung adenocarcinoma cell line, A549 wild type, and three sublines, A549-VP1-3, exposed to increasing concentrations of the topoisomerase II inhibitor, VP16. R-banding karyotype, fluorescence in situ hybridization (FISH), and Southern blot for the MLL gene were also performed. The CGH analysis showed that the A549-VP3 cell line shared chemoresistance-specific abnormalities (amplification of 11q23-qter, loss of chromosome 17, and deletions of 2p14-pter and 2q23-q24). FISH analysis confirmed the loss of one chromosome 17 in the three resistant sublines and revealed an increased fragmentation of chromosome 2 in more than two segments, depending on the etoposide concentration. FISH with an MLL gene probe showed additional signals of MLL (from three in the A549-WT to seven in the A549-VP3 cell line) translocated onto several other chromosomes. Southern blot indicated an amplification of the MLL gene, dependent on the etoposide concentration, without gene rearrangement. The CGH results are suggestive of loci that could be associated with the acquisition of an etoposide-chemoresistant phenotype. Deletion of the 2p region has already been reported, without any candidate gene being identified. The role of MLL in leukemogenesis has previously been demonstrated, but its role in the development of other tumors or its significance in the chemoresistance process remains to be elucidated.
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PMID:Identification of chromosomal loci associated with non-P-glycoprotein-mediated multidrug resistance to topoisomerase II inhibitor in lung adenocarcinoma cell line by comparative genomic hybridization. 1113 30

TEL-AML1 fusion resulting from the t(12;21)(p13;q22) is one of the most common genetic abnormalities in childhood acute lymphoblastic leukemia. Recent findings that site-specific cleavage of the MLL gene can be induced by chemotherapeutic agents such as topoisomerase-II inhibitors suggest that apoptogenic agents can cause chromosomal translocations in hematopoietic cells. This study demonstrates a possible relationship between exposure to apoptogenic stimuli, TEL breaks, and the formation of TEL-AML1 fusion in immature B lymphocytes. Short-term culture of immature B cell lines in the presence of apoptogenic stimuli such as serum starvation, etoposide, or salicylic acid induced double-strand breaks (DSBs) in intron 5 of the TEL gene and intron 1 of the AML1 gene. TEL-AML1 fusion transcripts were also identified by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis in cell lines treated by serum starvation or aminophylline. DSBs within the TEL gene were also associated with fusion to other unknown genes, presumably as a result of chromosomal translocation. We also examined 67 cord blood and 147 normal peripheral blood samples for the existence of in-frame TEL-AML1 fusion transcripts. One cord blood sample (1.5%) and 13 normal peripheral blood samples (8.8%) were positive as detected by nested RT-PCR. These data suggest that breakage and fusion of TEL and AML1 may be relatively common events and that sublethal apoptotic signals could play a role in initiating leukemogenesis via the promotion of DNA damage.
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PMID:Breakage and fusion of the TEL (ETV6) gene in immature B lymphocytes induced by apoptogenic signals. 1115 92

Therapy-related MDS and AML are complications of intensive chemotherapy regimens. Traditionally, patients exposed to topoisomerase II inhibitors are reported to develop secondary AML with abnormalities of chromosome 11q23. We evaluated the long-term hematologic toxicity of topoisomerase II-intensive high-dose mitoxantrone-based chemotherapy in 163 newly diagnosed acute leukemia patients treated over an 8 year period. Nine (5.5%) patients developed new cytogenetic abnormalities. Four patients developed MDS with progression to AML, three patients developed new abnormalities at the time of relapse, and three patients (including one of the former patients) had changes that were not associated with hematologic disease. The abnormalities most frequently involved chromosomes 7q, 20q, 1q, and 13q. Despite the use of topoisomerase II-intensive treatment, no patient developed an abnormality involving chromosome 11q23. Spontaneous resolution of some changes and prolonged persistence of others in the absence of hematologic disease indicates that some cytogenetic changes are not sufficient to promote leukemogenesis.
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PMID:Secondary acute myelogenous leukemia and myelodysplasia without abnormalities of chromosome 11q23 following treatment of acute leukemia with topoisomerase II-based chemotherapy. 1141 84

Elevated frequencies of chromosomal aberrations have been observed in the lymphocytes of benzene-exposed workers. Similar changes occurring in the bone marrow may play an important role in the development of leukemia. The objective of this research has been to characterize chromosomal alterations induced by benzene in mice and humans and to investigate the potential role of inhibition of topoisomerase II in the myelotoxic effects of benzene. The research is presented in three sections corresponding to the specific aims of the project: genotoxicity studies in the mouse, topoisomerase II studies, and initial studies using a new fluorescence in situ hybridization (FISH) approach to detect chromosome alterations in benzene-exposed workers. The results of the mouse experiments indicate that both chromosome breakage and aneuploidy are induced in the bone marrow of B6C3F1 mice following benzene administration. Chromosome breakage is the predominant effect, and this occurs primarily in the mouse euchromatin. Significant breakage within the mouse heterochromatin was also observed, as was aneuploidy. Breakage in the mouse bone marrow erythrocytes increased as a function of both dose and duration of benzene administration. The aneuploidy resulting from benzene exposure in mice was a relatively infrequent event, with increases of both chromosome loss and hyperdiploidy being observed. In the topoisomerase studies, benzene or its metabolites were shown to inhibit topoisomerase II enzyme activity in an isolated enzyme system, in a human bone marrow-derived leukemia cell line, and in vivo in the bone marrow of treated mice. The decreased activity was probably due to the rapid degradation of the topoisomerase II protein in the treated cells. In the human biomonitoring studies, the feasibility of using FISH with tandem DNA probes to detect chromosome alterations in interphase granulocytes and lymphocytes of benzene-exposed workers was demonstrated. The results from the two worker studies were somewhat inconsistent, however. In the study of Estonian workers, characterized by lower exposures and a smaller sample size, the benzene-exposed workers exhibited elevated frequencies of breakage in the lq12 region as compared with those seen in controls. A suggestive trend toward increased hyperdiploidy was also seen, although the frequencies in the exposed workers were low and within the range of our laboratory's historical control frequencies. In the larger study of more highly exposed Chinese workers, no increase in breakage affecting the 1q12 region was seen among the exposed workers. A trend toward increased hyperdiploidy of chromosome 1 was seen in the exposed workers when the concentration of urinary benzene metabolites was used in conjunction with the frequency of hyperdiploidy observed in the lymphocytes of the individual workers. The results of these studies indicate that benzene exposure is characterized by chromosome breakage, primarily within the euchromatin, and modest increases in aneuploidy. These findings also provide the first direct evidence that benzene is capable of inhibiting the enzymatic activity of topoisomerase II in vivo, providing additional support for the hypothesis that inhibition of topoisomerase II contributes to benzene-induced toxicity and leukemogenesis.
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PMID:Characterization and mechanisms of chromosomal alterations induced by benzene in mice and humans. 1150 46

The recurring chromosome translocation t(11;16)(q23;p13) is detected in leukemia patients, virtually all of whom have received previous chemotherapy with topoisomerase (topo) II inhibitors. In the t(11;16), 3' CBP, on 16p13, is fused to 5' MLL, on 11q23, resulting in an MLL-CBP fusion gene that plays an important role in leukemogenesis. In this study, we cloned genomic breakpoints of the MLL and CBP genes in the t(11;16) in the SN-1 cell line and in five patients with therapy-related leukemia, all of whom had received topo II inhibitors for previous tumors. In all patients except one, both the genomic MLL-CBP and the reciprocal fusions were cloned. Genomic breakpoints in MLL occurred in the 8.3-kb breakpoint cluster region in all patients, whereas the breakpoints in CBP clustered in an 8.2-kb region of intron 3 in four patients. Genomic breakpoints in MLL occurred in intron 11 near the topo II cleavage site in the SN-1 cell line and in one patient, and they were close to LINE repetitive sequences in two other patients. In the remaining two patients, genomic breakpoints were in intron 9 in Alu repeats. Genomic breakpoints in CBP occurred in and around Alu repeats in one and two patients, respectively. In two patients, the breaks were near LINE repetitive sequences, suggesting that repetitive DNA sequences may play a role. No specific recombination motifs were identified at or near the breakpoint junctions. No topo II cleavage sites were detected in introns 2 and 3 of CBP. However, there were deletions and duplications at the breakpoints in both MLL and CBP and microhomologies or nontemplated nucleotides at most of the genomic fusion junctions, suggesting that a nonhomologous end-joining repair mechanism was involved in the t(11;16).
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PMID:Characterization of genomic breakpoints in MLL and CBP in leukemia patients with t(11;16). 1533 49


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