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)

We report a case of therapy-related acute myeloid leukemia after low-dosed topoisomerase II inhibitor (etoposide) treatment for hemophagocytic lymphohistiocytosis (HLH). A 62-yr-old female patient had previously been treated with a HLH-94 protocol containing a low-dose of etoposide (total dose of 300 mg/m2). Thirty-one months later, the patient was admitted to the hematology department with general weakness and upper respiratory infection symptoms. Peripheral blood smear and bone marrow study revealed acute monocytic leukemia. There was no evidence of myelodysplastic syndrome, and a cytogenetic study showed no chromosomal abnormalities.
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PMID:[A case of therapy-related acute monocytic leukemia following low-dose of etoposide treatment for hemophagocytic lymphohistiocytosis]. 1809 83

Current APL chemotherapy protocols usually include high-dose anthracyclines, mitoxantrone, and epipodophillotoxins, which are topoisomerase II inhibitors of high leukemogenic potential. In the last years, several case reports of myelodysplastic syndrome (MDS) or AML (different from APL), occurring during the course of APL have been made. We report herein a first case of CMML with monosomy 7 occurring after treatment of APL.
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PMID:Secondary chronic myelomonocytic leukemia with monosomy 7 after successful treatment of acute promyelocytic leukemia. 1817 33

We prospectively observed a child exposed to intensive multimodality therapy for metastatic neuroblastoma from emergence of a MLL translocation to disease diagnosis. The t(4;11)(p12;q23) was detected in the marrow 17 months after starting treatment following topoisomerase II poisons, alkylating agents, local radiation, hematopoietic stem cell transplantation, anti-GD2 monoclonal antibody with granulocyte macrophage-colony-stimulating factor, and a high cumulative dose of oral etoposide. Reciprocal genomic breakpoint junctions and fusion transcripts joined MLL with FRYL, the Drosophila melanogaster protein homologue of which regulates cell fate. Etoposide metabolites induced topoisomerase II cleavage complexes that could form both breakpoint junctions. Cells harboring the translocation replaced the marrow without clinical evidence of leukemia and differentiation appeared unaffected for 37 months. Subsequent bilineage dysplasia and increased blasts in addition to the translocation fulfilled criteria for MDS. The MEIS1 target gene of typical MLL fusion oncoproteins was underexpressed before and at MDS diagnosis. These results are consistent with repair of topoisomerase II cleavage from etoposide metabolites as the translocation mechanism, whereas other agents in the regimen may have contributed to progression of the clone with the translocation to MDS. MLL-FRYL did not increase MEIS1 expression, conferred a proliferative advantage without altering differentiation, and had protracted latency to disease.
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PMID:Prospective tracing of MLL-FRYL clone with low MEIS1 expression from emergence during neuroblastoma treatment to diagnosis of myelodysplastic syndrome. 1819 96

Myelodysplasia (MDS) and acute myeloid leukemia (AML) are heterogeneous, closely associated diseases arising de novo or following chemotherapy with alkylating agents, topoisomerase II inhibitors, or after radiotherapy. Whereas de novo MDS and AML are almost always subclassified according to cytogenetic characteristics, therapy-related MDS (t-MDS) and therapy-related AML (t-AML) are often considered as separate entities and are not subdivided. Alternative genetic pathways were previously proposed in t-MDS and t-AML based on cytogenetic characteristics. An increasing number of gene mutations are now observed to cluster differently in these pathways with an identical pattern in de novo and in t-MDS and t-AML. An association is observed between activating mutations of genes in the tyrosine kinase RAS-BRAF signal-transduction pathway (Class I mutations) and inactivating mutations of genes encoding hematopoietic transcription factors (Class II mutations). Point mutations of AML1 and RAS seem to cooperate and predispose to progression from t-MDS to t-AML. Recently, critical genetic effects underlying 5q-/-5 and 7q-/-7 have been proposed. Their association and cooperation with point mutations of p53 and AML1, respectively, extend the scenario of cooperating genetic abnormalities in MDS and AML. As de novo and t-MDS and t-AML are biologically identical diseases, they ought to be subclassified and treated similarly.
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PMID:Genetics of therapy-related myelodysplasia and acute myeloid leukemia. 1820 41

Treatment of acute promyelocytic leukemia (APL) with a combination of anthracycline-based chemotherapy and all-trans retinoic acid (ATRA) leads to very high rates of complete remission and survival. There are only a limited number of publications on the development of therapy-related myelodysplastic syndrome (MDS) or acute myeloid leukemia during follow-up of APL. Although drugs targeting at DNA-topoisomerase II characteristically induce translocations involving 11q23, this was seldom seen in patients treated for APL. We report on a patient initially diagnosed with APL. Response to therapy was monitored by fluorescence in situ hybridization (FISH) and reverse-transcriptase polymerase chain reaction for the PML-RARalpha rearrangement. Consecutive samples showed a swift and complete reduction of PML-RARalpha rearranged cells. Twenty months after diagnosis, however, conventional cytogenetics revealed a complex karyotype with a translocation involving 11q23 and loss of chromosomes 7q and Xq. FISH analysis with the MLL probe identified 2q37 (harboring the SEPT2 gene) as the translocation partner of chromosome 11. We consider the rather unique t(2;11)(q37;q23) as the primary event causing therapy-related MDS in our patient. This case stresses the importance of conventional karyotyping to be performed on a regular basis in all treated APL patients for the early detection of chromosomal aberrations that indicate the development of therapy-related MDS or acute myeloid leukemia.
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PMID:Translocation (2;11)(q37;q23) in therapy-related myelodysplastic syndrome after treatment for acute promyelocytic leukemia. 1820 42

Therapy-related myelodysplasia and acute myeloid leukemia (t-MDS/AML) are malignancies occurring after exposure to chemotherapy and/or radiotherapy. Several studies have addressed cumulative dose, dose intensity and exposure to specific agents of preceding cytotoxic therapy in relation to the risk of developing such leukemia. Since only a small percentage of patients exposed to cytotoxic therapy develop t-MDS/AML, it has been suggested that some genetic predisposition may be involved, specifically associated to polymorphisms in certain genes involved in chemotherapy/radiotherapy response - fundamentally genes intervening in drug detoxification and DNA synthesis and repair. A review is made of the genetic studies related to t-MDS/AML predisposition, focusing on the mechanistic findings of how specific chemotherapeutic drug exposure produces DNA damage and induces the chromosomal abnormalities characteristic of t-MDS/AML, the molecular pathways involved in repairing such drug induced damage, and the way in which they influence t-MDS/AML genesis. Specific issues are (a) the interaction of topoisomerase II inhibitors, alkylators and antimetabolite drugs with DNA repair mechanisms and their impact on t-MDS/AML leukemogenicity and (b) the influence of DNA polymorphisms in genes involved in DNA repair, drug metabolization and nucleotide synthesis, paying special attention to the relevance of folate metabolism. Finally, we discuss some aspects relating to study design that are most suitable for characterizing associations between drug exposure and genotypes related to t-MDS/AML risk - stressing the importance of the inclusion of chemotherapy-exposed control groups.
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PMID:Influence of DNA damage and repair upon the risk of treatment related leukemia. 1823 6

Advances in the therapy of malignancy have been accompanied by an increased frequency of cases of secondary acute myelogenous leukemia and related clonal cytopenias and oligoblastic (subacute) myelogenous leukemia (myelodysplastic syndromes). The acute myelogenous leukemia incidence can be increased by high-dose acute ionizing radiation exposure, alkylating agents, topoisomerase II inhibitors, possibly other DNA-damaging therapeutic agents, heavy, prolonged cigarette smoking, and high dose-time exposure to benzene, the latter less frequently seen in industrialized countries with worksite regulations. Acute myelogenous leukemia and myelodysplastic syndromes may result from innumerable primary types of chromosome damage. In the case of chronic myelogenous leukemia, a specific break in chromosome bands 9q34 and 22q11 must occur to result in the causal fusion oncogene (BCR-ABL). A review of 11 studies of the chromosomal abnormalities found in presumptive cases of cytotoxic therapy-induced leukemia and of 40 studies of the subtypes of leukemia that occur following cytotoxic therapy for other cancers has not provided evidence of an increased risk for chemically induced BCR-ABL-positive chronic myelogenous leukemia. Studies of the effects of alkylating agents, topoisomerase inhibitors, and benzene on chromosomes of hematopoietic cells in vitro, coupled with the aforementioned epidemiological studies of secondary leukemia after cytotoxic therapy or of persons exposed to high dose-time concentrations of benzene in the workplace, do not indicate a relationship among chemical exposure, injury to chromosome bands 9q34 and 22q11, and an increased risk for BCR-ABL-positive chronic myelogenous leukemia.
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PMID:Is there an entity of chemically induced BCR-ABL-positive chronic myelogenous leukemia? 1858 19

Administration of alkylating agents (Alk), topoisomerase II inhibitors (Topo II) and radiotherapy (RT) can result in therapy-related myelodysplastic syndrome or acute myelogenous leukaemia (t-MDS/t-AML), the optimal treatment for which is allo-SCT. A retrospective review was performed of 24 patients who underwent related- or unrelated-donor SCT for t-MDS/t-AML at our institution. Eight patients remain alive and in continuous remission (median follow-up 54 months (range, 12-161)) with estimated 5-year EFS being 30% (95% confidence intervals 16-58%). Corresponding actuarial risks of relapse and non-relapse mortality (NRM) are 39% (19-60%) and 30% (13-50%), respectively. EFS was 40% in Alk/RT-related t-MDS/t-AML and 11% in Topo II-related t-MDS/t-AML (P=0.05), with an increased risk of relapse in the latter (56 vs 29%, respectively (P=0.05)). In multivariate analysis, development of acute GVHD (P=0.009) and Topo II-related t-MDS/t-AML (P=0.018) were associated with inferior EFS. Patients with acute GVHD had an increased risk of NRM (P=0.03) whereas risk of relapse was higher for patients of advanced age (P=0.046) and for patients who underwent bone marrow (vs blood) SCT (P=0.032). Allo-SCT can result in long-term survival for individuals with t-MDS/t-AML although outcome in Topo II-related t-MDS/t-AML patients remains suboptimal.
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PMID:Predictors of outcome following myeloablative allo-SCT for therapy-related myelodysplastic syndrome and AML. 1867 72

Translocations and other rearrangements of the MLL gene at chromosome band 11q23 are biologically and clinically important molecular abnormalities in infant acute leukemias, leukemias associated with chemotherapeutic topoisomerase II poisons and, less often, acute leukemias in adults or myelodysplastic syndrome. Depending on the disease and the regimen, MLL-rearranged leukemias may be associated with inferior prognosis, and MLL rearrangements with some of the more than 60 known MLL-partner genes confer especially adverse effects as response to treatment (Blood 108:441-451, 2006). MLL rearrangements are usually evident as overt balanced chromosomal translocations by conventional cytogenetic analysis but up to one-third are cryptic rearrangements and occur in leukemias with del(11)(q23), a normal karyotype, or trisomy 11, the latter two of which sometimes are associated with partial tandem duplications of MLL itself (Proc Natl Acad Sci USA 97:2814-2819, 2000; Proc Natl Acad Sci USA 94:3899-3902, 1997). In addition, subsets of MLL rearrangements are complex at a cytogenetic level and/or molecular level, and fuse MLL with two different partner genes. Rapid and accurate methods to identify and characterize genomic breakpoint junctions and fusion transcripts resulting from the many types of MLL rearrangements are essential for risk group stratification, treatment protocol assignments, new partner gene discovery, understanding leukemia etiology and pathogenesis, and elucidating the impact of less common MLL-partner genes on biology and prognosis. Due to the vast heterogeneity in partner genes, typical gene-specific PCR based methods are not practical, especially when cytogenetics are normal or do not suggest involvement of a known partner gene of MLL. We have advanced seven different panhandle PCR based methods for cloning 5'-MLL-partner gene-3' and 5'-partner gene-MLL-3' genomic breakpoint junctions and identifying 5'-MLL-partner gene-3' fusion transcripts, all of which employ a stem-loop template shaped schematically like a pan with a handle and amplify the template without knowledge of the unknown partner sequence using primers all derived from MLL alone.
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PMID:Panhandle PCR approaches to cloning MLL genomic breakpoint junctions and fusion transcript sequences. 1927 75

Radiation induced acute myeloid leukemia (AML) was recognized a century ago, soon after mankind found radiation. Atomic bomb survivors developed de novo AML with relatively short latency with very high frequency. By contrast, excess occurrence of myelodysplastic syndrome (MDS) as well as solid tumors was found decades late. This difference may be due to etiology that many de novo AML patients harbor chimeric leukemogenic genes caused by chromosomal translocations, while MDS patients rarely carry chimeras. In addition, epigenetic change would play important roles. Therapy related leukemia is mainly caused by topoisomerase II inhibitors that cause de novo AML with an 11q23 translocation or by alkyrating agents that induce MDS/AML with an AML1 point mutation and monosomy 7.
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PMID:[Radiation-induced and therapy-related AML/MDS]. 1986 Jan 83


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