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)

Leukemias with MLL gene translocations are a complication of primary cancer treatment with DNA topoisomerase II inhibitors. How early translocations appear during primary cancer treatment has not been investigated. We tracked the leukemic clone with an MLL gene translocation during neuroblastoma therapy in a child who developed acute myeloid leukemia. The karyotype of the leukemic clone showed del(11)(q23). We used panhandle PCR-based methods to isolate the breakpoint junction involving MLL and an unknown partner gene. Marrow DNA from neuroblastoma diagnosis and DNA and RNA from serial preleukemic marrows were examined for the translocation. The karyotypic del(11)(q23) was a cryptic t(11;17). GAS7, a growth arrest-specific gene at chromosome band 17p13, was the partner gene of MLL. Two different MLL-GAS7 fusion transcripts were expressed. The translocation was already detectable by 1.5 months after the start of neuroblastoma treatment. The translocation was not detectable in the marrow at neuroblastoma diagnosis or in peripheral blood lymphocyte DNAs of six normal subjects. GAS7 is a new partner gene of MLL in treatment-related acute myeloid leukemia. MLL gene translocations can be present early during anticancer treatment at low cumulative doses of DNA topoisomerase II inhibitors. Although MLL has many partner genes and most have not been characterized, panhandle PCR strategies afford new means for detecting MLL gene translocations early during therapy when the partner gene is unknown.
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PMID:Detection of leukemia-associated MLL-GAS7 translocation early during chemotherapy with DNA topoisomerase II inhibitors. 1070 19

It is known that alkylating agents and topoisomerase II inhibitors can cause distinct forms of therapy-related leukemia and myelodysplastic syndrome (TRL/MDS). Although several reports have been made on each of these agents separately, no study has yet been conducted to evaluate the effect of these two types of agents in the same population. In a nationwide, large-scale population study, the clinical and cytogenetic features as well as the prognostic factors in 256 patients with TRL/MDS were assessed. Median age was 61 years, and the median period of latency from primary malignancies was 47.9 months. The latency period was significantly shorter in patients undergoing chemotherapy, especially that of topoisomerase II inhibitors, for primary cancer. The morphological diagnosis of TRL/MDS was acute myeloid leukemia in 59% and MDS in 41% of patients. Chromosome abnormalities that frequently involved chromosomes 5, 7 or 11 were documented in 77% of the 189 patients examined. MLL gene rearrangements were detected in 11 of 58 subjects and were correlated with a borderline significance (P = 0.072) with topoisomerase II inhibitor administration. Overall median survival was only 9.7 months. Survival was similar in cases with or without MLL gene rearrangement. Multivariate analysis identified chromosome 5 abnormalities, hypoproteinemia, poor therapy outcomes for primary cancer, C-reactive protein, and thrombocytopenia as being significantly poor prognostic factors (P < 0.05). This large-population study provided a comprehensive update of TRL/MDS status in Japan, identified significant prognostic factors, and enabled the clinical significance of MLL gene rearrangement to be assessed.
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PMID:Therapy-related leukemia and myelodysplastic syndrome: a large-scale Japanese study of clinical and cytogenetic features as well as prognostic factors. 1074 24

Gene CBP codes for a transcriptional coactivator, which can interact with many transcriptional factors. It modifies the process of transcription stimulated by these factors by specific binding to RNA polymerase II holoenzyme or by histone acetylation. CBP gene mutation is the molecular cause of autosomal dominant genetic disease called Rubinstein-Taybi syndrome that is manifested by mental and growth retardations, by typical face malformations and broad thumbs and broad big toes. The CBP gene can be affected by the t(8;16)(p11;p13.3) translocation resulting in production of the MOZ/CBP chimeric protein and in induction of acute myeloblastic leukaemia. Therapy using topoisomerase II inhibitors can induce the t(11;16)(q23;13.3) translocation causing acute myeloid or lymphoid leukaemia or myelodysplasia through production of the MLL/CBP protein chimera.
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PMID:[Clinical sequelae of mutation of the CBP gene]. 1074 38

Chromosomal translocations involving the MLL gene occur in about 80% of infant leukemia. In the search for possible agents inducing infant leukemia, we identified bioflavonoids, natural substances in food as well as in dietary supplements, that cause site-specific DNA cleavage in the MLL breakpoint cluster region (BCR) in vivo. The MLL BCR DNA cleavage was shown in primary progenitor hematopoietic cells from healthy newborns and adults as well as in cell lines; it colocalized with the MLL BCR cleavage site induced by chemotherapeutic agents, such as etoposide (VP16) and doxorubicin (Dox). Both in vivo and additional in vitro experiments demonstrated topoisomerase II (topo II) as the target of bioflavonoids similar to VP16 and Dox. Based on 20 bioflavonoids tested, we identified a common structure essential for topo II-induced DNA cleavage. Reversibility experiments demonstrated a religation of the bioflavonoid as well as the VP16-induced MLL cleavage site. Our observations support a two-stage model of cellular processing of topo II inhibitors: The first and reversible stage of topo II-induced DNA cleavage results in DNA repair, but also rarely in chromosome translocations; whereas the second, nonreversible stage leads to cell death because of an accumulation of DNA damage. These results suggest that maternal ingestion of bioflavonoids may induce MLL breaks and potentially translocations in utero leading to infant and early childhood leukemia.
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PMID:Dietary bioflavonoids induce cleavage in the MLL gene and may contribute to infant leukemia. 1078 Oct 30

With optimum treatment 65-70% of children diagnosed with cancer should be long term survivors and probably cured. Prevention is better than cure. Recent studies into the causes of childhood malignancy are reviewed. The incidence of childhood acute lymphoblastic leukaemia (ALL) is steadily increasing. The cause for this may be increasing social and economic development. Exposure to electromagnetic fields has been a cause of concern for almost 20 years. A recent large case control study has shown no increased risk of cancer or leukaemia in those who have measurably increased exposure to electromagnetic fields. Leukaemia which has the cytogenetic abnormality 11q23 or MLL gene rearrangement characteristically occurs as a second malignancy after exposure to epipodophyllotoxins which act by inhibiting topoisomerase. Infant leukaemia has the same cytogenetic profile. Mothers of babies who develop infant leukaemia have high exposure to potential dietary inhibitors of topoisomerase during pregnancy. Clusters of leukaemia can probably best be accounted for by population mixing. There may be an increased risk of ALL following vitamin K given to newborns.
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PMID:Childhood cancer: improved prospects for survival but is prevention possible? 1077 43

The MLL gene at 11q23 is frequently disrupted by chromosomal translocations in de novo acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL), and in secondary leukemia induced by treatment with inhibitors of topoisomerase II, including the epipodophylotoxins. The CBFA2 gene at 21q22 is also frequently disrupted in de novo ALL and AML and less commonly in secondary AML. Rearrangements of MLL and CBFA2 have been described in de novo and secondary myelodysplastic syndrome (MDS). There have been no previous descriptions of coexisting abnormalities of MLL and CBFA2 in cases of MDS or acute leukemia. We describe a patient who developed secondary MDS after chemotherapy for hyperdiploid ALL. At the time of conversion to MDS, the patient had 46 chromosomes, with an 11q23/MLL translocation involving a new partner breakpoint at 2p23 and a 21q22/CBFA2 translocation involving a new partner breakpoint at 6p22. This report is the first to describe new partner breakpoints at 2p23 and 6p22 for MLL and CBFA2 genes, respectively, and concurrent rearrangements of these genes in a patient with secondary MDS.
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PMID:Concurrent translocations of MLL and CBFA2 (AML1) genes with new partner breakpoints in a child with secondary myelodysplastic syndrome after treatment of acute lymphoblastic leukemia. 1082 8

The partner gene of MLL was identified in a patient with treatment-related acute myeloid leukemia in which the karyotype suggested t(3;11)(q25;q23). Prior therapy included the DNA topoisomerase II inhibitors, teniposide and doxorubicin. Southern blot analysis indicated that the MLL gene was involved in the translocation. cDNA panhandle polymerase chain reaction (PCR) was used, which does not require partner gene-specific primers, to identify the chimeric transcript. Reverse-transcription of first-strand cDNAs with oligonucleotides containing known MLL sequence at the 5' ends and random hexamers at the 3' ends generated templates with an intra-strand loop for PCR. In-frame fusions of either MLL exon 7 or exon 8 with the GMPS (GUANOSINE 5'-MONOPHOSPHATE SYNTHETASE) gene from chromosome band 3q24 were detected. The fusion transcript was alternatively spliced. Guanosine monophosphate synthetase is essential for de novo purine synthesis. GMPS is the first partner gene of MLL on chromosome 3q and the first gene of this type in leukemia-associated translocations. (Blood. 2000;96:4360-4362)
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PMID:t(3;11) translocation in treatment-related acute myeloid leukemia fuses MLL with the GMPS (GUANOSINE 5' MONOPHOSPHATE SYNTHETASE) gene. 1111 Jul 14

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

Leukemic cells have been shown to generate several classes of DNA fragments after treatment with cytotoxic cancer chemotherapy agents. However, it is unclear which of these fragmentation events are a direct effect of DNA-damaging chemotherapy agents, and which fragmentation events are caused by downstream processes, such as apoptosis. We have performed a detailed analysis of DNA fragmentation events which occur following cytotoxic chemotherapy in four representative leukemic cell lines (HL-60, Jurkat, K562, and Molt-4). We used a DNA topoisomerase II inhibitor (etoposide), an alkylating agent (melphalan), a nucleoside analog (cytosine arabinoside), and a non-genotoxic agent (N-methylformamide) to induce cell death. We studied high molecular weight and low molecular weight DNA fragmentation events, as well as the specific cleavage of the MLL breakpoint cluster region (bcr). The DNA fragments produced at late time points were largely independent of the agents used, while those generated at earlier time points showed clear differences in terms of fragment size and relative abundance, depending on the agent used. In addition, there were clear differences between cell lines in terms of size, relative abundance, and rate at which DNA fragments were produced by treatment with the same agents. We think that this survey documents the importance of studying several different cell lines, time points, and assays before reaching conclusions about the types of DNA fragments produced during treatment with cytotoxic agents, and provides a useful framework for studying a wide range of DNA fragments produced by cytotoxic agents.
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PMID:Characterization of DNA fragmentation events caused by genotoxic and non-genotoxic agents. 1116 35


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