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:5.99.1.2 (topoisomerase)
9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mixed lineage leukemia, MLL, gene is frequently rearranged in patients with secondary leukemia following treatment with DNA topoisomerase II inhibitors. By FISH and Southern blot analyses we identified a rearrangement in the MLL gene due to a novel t(3;11)(q28;q23) chromosomal translocation in a patient who developed AML-M5 3 years after treatment for a follicular lymphoma. Through inverse PCR, the LPP (lipoma preferred partner) gene on 3q28 was identified as the MLL fusion partner. LPP contains substantial identity to the focal adhesion protein, zyxin, and is frequently fused to HMGIC in lipomas. The breakpoint occurred in intron 8 of MLL and LPP. Two in-frame MLL-LPP transcripts, which fuse MLL exon 8 to LPP exon 9, were detected by RT-PCR, although the smaller of these contained a deletion of 120 bp from the MLL sequence. The predicted MLL-LPP fusion protein includes the A/T hook motifs and methyltransferase domain of MLL joined to the two last LIM domains of LPP. A reciprocal LPP-MLL transcript, predicted to include the proline-rich and leucine zipper motifs, and the first LIM domain of LPP were also detected by RT-PCR. In summary, LPP is a newly identified MLL fusion partner in secondary leukemia resulting from topoisomerase inhibitors. The MLL-LPP and LPP-MLL predicted proteins contain many of the features present in other MLL rearrangements.
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PMID:Human LPP gene is fused to MLL in a secondary acute leukemia with a t(3;11) (q28;q23). 1143 29

We analyzed the der(11) and der(4) genomic breakpoint junctions of a t(4;11) in the leukemia of a patient previously administered etoposide and dactinomycin by molecular and biochemical approaches to gain insights about the translocation mechanism and the relevant drug exposure. The genomic breakpoint junctions were amplified by PCR. Cleavage of DNA substrates containing the normal homologues of the MLL and AF-4 translocation breakpoints was examined in vitro upon incubation with human DNA topoisomerase IIalpha and etoposide, etoposide catechol, etoposide quinone, or dactinomycin. The der(11) and der(4) genomic breakpoint junctions both involved MLL intron 6 and AF-4 intron 3. Recombination was precise at the sequence level except for the overall gain of a single templated nucleotide. The translocation breakpoints in MLL and AF-4 were DNA topoisomerase II cleavage sites. Etoposide and its metabolites, but not dactinomycin, enhanced cleavage at these sites. Assuming that DNA topoisomerase II was the mediator of the breakage, processing of the staggered nicks induced by DNA topoisomerase II, including exonucleolytic deletion and template-directed polymerization, would have been required before ligation of the ends to generate the observed genomic breakpoint junctions. These data are inconsistent with a translocation mechanism involving interchromosomal recombination by simple exchange of DNA topoisomerase II subunits and DNA-strand transfer; however, consistent with reciprocal DNA topoisomerase II cleavage events in MLL and AF-4 in which both breaks became stable, the DNA ends were processed and underwent ligation. Etoposide and/or its metabolites, but not dactinomycin, likely were the relevant exposures in this patient.
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PMID:Near-precise interchromosomal recombination and functional DNA topoisomerase II cleavage sites at MLL and AF-4 genomic breakpoints in treatment-related acute lymphoblastic leukemia with t(4;11) translocation. 1149 4

Therapy-related acute myeloid leukemias (t-AML) with translocations of the MLL gene are associated with the use of topoisomerase II inhibitors. We established the emergence of the malignant clone in a child who developed t-AML with a t(11;19) (q23;p13.3) during treatment for acute lymphoblastic leukemia (ALL). The MLL-ENL and the reciprocal ENL-MLL genomic fusions and their chimeric transcripts were characterized from samples collected at the time of t-AML diagnosis. We used PCR with patient-specific genomic primers to establish the emergence of the MLL-ENL fusion in serially obtained DNA samples. The MLL-ENL fusion was not detectable in bone marrow at the time of ALL diagnosis or after 2 months of chemotherapy (frequency <8.3 x 10(-7) cells(-1)). The genomic fusion was first detected in bone marrow after 6 months of treatment at a frequency of one in 4,000 mononuclear bone marrow cells; the frequency was one in 70 cells after 20 months of therapy. At the first detection of MLL-ENL, the only topoisomerase II inhibitors the patient had received were one dose of daunorubicin and two doses of etoposide. The MLL-ENL fusion was not detectable in blood at the time of ALL diagnosis or after 0.7, 2, 8, 10, and 12 months of therapy but was detectable in blood at 16 months (one in 2.3 x 10(4) cells). Recombinogenic Alu sequences bracketed the breakpoints in both fusions. These data indicate that the malignant clone was not present before therapy, arose early during chemotherapy, and was able to proliferate even during exposure to antileukemic therapy.
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PMID:Molecular emergence of acute myeloid leukemia during treatment for acute lymphoblastic leukemia. 1152 40

A highly increased risk of myelodysplasia (MDS) and acute myeloid leukaemia (AML) is well established in patients previously treated for other malignancies with alkylating agents or topoisomerase II inhibitors. More recently, single cases of acute lymphoblastic leukaemia (ALL), often presenting balanced translocations involving chromosome band 11q23, have been observed. We present two such cases with t(4;11)(q21;q23), one of whom had previously received only single-agent chemotherapy with 4-epi-doxorubicin. A review of the literature since 1992 including these two patients reveals a total of 23 cases of ALL or lymphoblastic lymphoma after chemotherapy presenting balanced translocations to 11q23. All 23 patients had previously received at least one topoisomerase II inhibitor, and in two patients 4-epi-doxorubicin had been administered as single-agent chemotherapy for breast cancer. The latency period to development of t-ALL was 24 months or less in 20 out of 22 cases. The MLL gene was found to be rearranged in 14 out of 14 cases, and in three out of six cases the breakpoint was at the telomeric part of the gene, as observed in most cases of AML following therapy with topoisomerase II inhibitors. These results indicate that patients with ALL and balanced translocations to chromosome band 11q23 following chemotherapy with topoisomerase II inhibitors in the future should be included with cases of MDS or AML in calculations of risk of leukaemia.
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PMID:Therapy-related acute lymphoblastic leukaemia with MLL rearrangements following DNA topoisomerase II inhibitors, an increasing problem: report on two new cases and review of the literature since 1992. 1155 77

We report a novel MLL-associated chromosome translocation t(11;14)(q23;q24) in a child who showed signs of acute undifferentiated leukemia 3 years after intensive chemotherapy that included the topoisomerase-II inhibitor VP 16. Screening of a cDNA library of the patient's leukemic cells showed a novel fusion transcript between MLL and the Gephyrin (GPHN) gene on 14q24. The resulting MLL-GPHN fusion gene encodes MLL AT hook motifs and a DNA methyltransferase homology domain fused to the C-terminal half of Gephyrin, including a presumed tubulin binding site and a domain homologous to the Escherichia coli molybdenum cofactor biosynthesis protein MoeA. Genomic breakpoint analysis showed potential in vitro topoisomerase-II DNA-binding sites spanning the breakpoints in both MLL and GPHN but no flanking sequences that might mediate homologous recombination. This suggests that MLL-GPHN may have been generated by VP 16/topoisomerase-II-induced DNA double-strand breaks, followed by error-prone DNA repair via non-homologous end joining. Gephyrin was originally identified as a submembraneous scaffold protein that anchors and immobilizes postsynaptic membrane neurotransmitter receptors to underlying cytoskeletal elements. It also is reported to bind to phosphatidylinositol 3,4,5-triphosphate binding proteins involved in actin dynamics and downstream signaling and interacts with ATM-related family member RAFT1. Gephyrin domains in the chimeric protein therefore could contribute novel signal sequences or might modify MLL activity by oligomerization or intracellular redistribution.
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PMID:GPHN, a novel partner gene fused to MLL in a leukemia with t(11;14)(q23;q24). 1157 61

The translocation t(4;11)(q21;q23) is one of the most frequent 11q23 abnormalities associated with infant leukaemia as well as topoisomerase inhibitor-induced secondary leukaemias. On the molecular level, the MLL gene on 11q23 is fused to the AF4 gene in the 4q21 region, resulting in a chimaeric MLL/AF4 fusion transcript. These particular chromosome rearrangements are generally considered to be associated with poor prognosis, and therefore accurate detection at diagnosis is of clinical significance. In this study we developed a highly specific dual-colour fluorescence in situ hybridization (FISH) assay for the detection of the t(4;11) and demonstrate its usefulness for interphase molecular cytogenetics. In our approach, differentially labelled genomic clones that span the breakpoint cluster regions of both genes involved in the specific translocation were used. Thus, t(4;11)-positive nuclei will display two fusion signals and for t(4;11) cases with concurrent 3' MLL deletions only one fusion signal will be displayed. A very low false-positive value of less than 0.1% was obtained for interphase cells with two fusion signals. In contrast, in cases with 3' MLL deletions that display only one fusion signal, the rate of false-positive nuclei was 10.4%. This FISH assay enables the screening of larger series of patients with haematological diseases for t(4;11) translocations and allows the unambiguous detection of associated cryptic deletions.
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PMID:A highly specific and sensitive fluorescence in situ hybridization assay for the detection of t(4;11)(q21;q23) and concurrent submicroscopic deletions in acute leukaemias. 1188 78

We report a case of acute myelogenous leukemia (AML) with MLL (myeloid-lymphoid leukemia or mixed-lineage leukemia) gene rearrangement after exposure to tegafur/uracil. Cytogenetic and clinical findings in this patient: t(11;17) (q23;q25), AML-M4 morphology, development of AML within a short latent period after first exposure to tegafur/uracil, and good response to remission induction chemotherapy but short remission duration, have been considered typical features of therapy-related acute myelogenous leukemia (t-AML) after exposure to topoisomerase II-targeting agents. This case report suggests that t-AML may develop after exposure to tegafur/uracil and that MLL gene rearrangement may not necessarily be specific to t-AML after exposure to topoisomerase II-targeting agents.
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PMID:MLL gene rearrangement in acute myelogenous leukemia after exposure to tegafur/uracil. 1193 65

Two main forms of therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/AML) have been recognized. The most frequent type, occurring after treatment with alkylating agents, is characterized by abnormalities of chromosomes 5 and/or 7 and t-MDS/AML following treatment with topoisomerase II inhibitors and is associated with molecular aberrations of MLL (11q23) and AML-1 (21q22). Individuals with certain polymorphisms associated with impaired detoxification of cytotoxic agents have an increased risk of developing MDS or AML after treatment of unrelated cancers. Multidrug chemotherapy is less effective for patients with MDS, or AML following MDS, or t-MDS/AML when compared with primary AML, and results in lower complete remission (CR) rates and lower long-term survival. Patients with good risk cytogenetic features, such as t(15; 17), t(8; 21) and inversion 16 are an exception as their treatment outcome is comparable with primary AML patients. Patients who attain a polyclonal and/or a cytogenetic CR may be candidates for autologous stem cell transplantation. For the remaining patients, the only curative option is allogeneic stem cell transplantation with stem cells from a histocompatible sibling or an alternative donor. Reduced intensity conditioning regimens may be considered for patients older than 50 years or patients with comorbidities. The advice is to treat patients early after diagnosis and preferably before progression as these patients have the highest chance of a favorable outcome.
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PMID:Stem cell transplantation for leukemias following myelodysplastic syndromes or secondary to cytotoxic therapy. 1206 Apr 85

The correlation between infant leukemia and in utero exposure to topoisomerase II (topo-II) inhibitor has been clarified. We examined the in vitro effect of topo-II inhibitor (etoposide) on cleavage of the MLL gene in cord and peripheral blood mononuclear cells (MNCs). Southern blot analysis showed cleavage of the MLL gene in peripheral blood MNCs of infants when the MNCs were exposed to etoposide. MNCs were incubated with etoposide at various concentrations (1 to 50 microM), and a ligation-mediated polymerase chain reaction (LM-PCR) was used to detect double strand breaks (DSBs) of DNA in intron 8 of the MLL breakpoint cluster region. PCR products obtained with LM-PCR were subcloned and sequenced to identify the breakpoint in the MLL gene. The PCR products indicated DSBs of the MLL gene were obtained without any difference in the incidence between 3 different samples (cord and peripheral blood from infants and children). Sequencing analysis showed that the DSBs occurred on the telomeric side of intron 8 and near exon 9. There was no evidence that the cord blood was more susceptible to MLL DNA breakage by topo-II inhibitor than were other cells. Instability of the partner gene during the fetal period could be associated with the pathogenesis of infant leukemia.
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PMID:In vitro cleavage of the MLL gene by topoisomerase II inhibitor (etoposide) in normal cord and peripheral blood mononuclear cells. 1213

The translocation t(9;11)(p22;q23) is a recurring chromosomal abnormality in acute myeloid leukemia (AML) fusing two genes designated as MLL and AF9. Within MLL, almost all rearrangements cluster in an 8.3-kb restricted region and fuse 5' portions of MLL to a variety of heterologous genes in various 11q23 translocations. AF9 is one of the most common fusion partners of MLL. It spans more than 100 kb, and two breakpoint cluster regions (BCRs) have been identified in a telomeric region of intron 4 (BCR1) and within introns 7 and 8 (BCR2). We investigated 11 children's bone marrow or peripheral blood samples (3 AML, 5 t-AML, 2 ALL, 1 ALL relapse) and two cell lines (THP-1 and Mono-Mac-6) with cytogenetically diagnosed translocations t(9;11). By use of an optimized multiplex nested long-range PCR assay, a breakpoint-spanning DNA fragment from each sample was amplified and directly sequenced. In four patients and two cell lines, the AF9 breakpoints were located within BCR1 and in two patients within BCR2, respectively. However, in five patients the AF9 breakpoints were found outside the previously described BCRs within the centromeric region of intron 4 and even within intron 3 in one case. All five patients with a secondary AML, who had not received etoposides during treatment of the primary malignant disease, revealed almost identical MLL breakpoints very close to a breakage hot spot inducible by topoisomerase II inhibitors or apoptotic triggers in vitro. Sequence patterns around the breakpoints indicated involvement of a "damage-repair mechanism" in the development of t(9;11) similar to t(4;11) in infants' acute leukemia.
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PMID:Analysis of t(9;11) chromosomal breakpoint sequences in childhood acute leukemia: almost identical MLL breakpoints in therapy-related AML after treatment without etoposides. 1261 63


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