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)

Acute promyelocytic leukemia (APL) is characterized by a specific chromosome translocation t(15;17). Recently, using molecular biology techniques, a number of laboratories have demonstrated that the gene coding for the retinoic acid receptor alpha (RARA), normally located on chromosome 17, is disrupted by the t(15;17) and fused with the PML gene on chromosome 15. The chromosome 17 breaks were mapped consistently within the second intron of the RARA gene while the chromosome 15 breaks were clustered in two limited regions within the PML gene. Molecular cloning and sequence analysis of the PML gene demonstrated a complex splicing pattern and this gene may encode a transcription factor. Different isoforms of the PML-RARA fusion transcripts were discovered which are produced as a result of distinct PML gene rearrangements. Sequence analysis of the reciprocal products of the translocation t(15;17) in some APL cases suggested the implication of topoisomerase II in mediating the DNA recombination. The RT/PCR procedure has been established to characterize the expression patterns of the PML-RARA fusion gene and to detect minimal residual disease (MRD). The biological activity of the PML-RARA fusion gene and its isoforms should be further explored.
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PMID:RARA and PML genes in acute promyelocytic leukemia. 133 47

Molecular studies of chromosomal translocation (15;17) in acute promyelocytic leukemia (APL) have shown that retinoic acid receptor A (RARA) gene on chromosome 17 is juxtaposed to the PML gene on chromosome 15. This results in a PML-RARA chimeric gene. Our work has demonstrated that the PML breakpoints in APL patients are clustered in two limited regions, PML-bcr1 and PML-bcr2, separated from each other by about 10 kb. DNA sequence of PML-bcr1 and primary structure of the junctional region of reciprocal chromosomal translocation in a patient have been determined in this paper. Compared to those of two previously reported cases abroad, we found that the breakpoint may be situated in the topoisomerase II cleavage site. A working model has been proposed for the mechanism of DNA illegitimate recombination in t (15;17).
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PMID:[Molecular study of the mechanism of chromosomal translocation (15;17) in acute promyelocytic leukemia (APL)]. 816 69

Progressive multifocal leukoencephalopathy is a subacute demyelinating disease of the central nervous system (CNS) resulting from opportunistic infections in immunocompromised patients infected with a common polyomavirus, JC virus (JCV). Unlike other polyomaviruses, JCV exhibits an unusually narrow tissue tropism by primarily infecting glial cells of the CNS. JCV DNA replication is similar to that of the well-characterized papovavirus, SV40, which requires the viral early protein T-antigen and host-replication factors including DNA polymerases and DNA topoisomerase I. In this study we have been able to effectively block replication of viral DNA in glial cells using camptothecin, a drug which inhibits DNA topoisomerase activity. Pulse-treatment of cells with non-toxic levels of camptothecin specifically blocks viral DNA replication with no inhibitory effect on host transcription and translation processes as examined by viral gene expression in the transfected cells. Furthermore, drug treatment of the cells exhibits no significant effect on DNA topoisomerase I gene transcription. We further demonstrate that repeated pulse-treatment of cells with the drug is required for complete blockage of viral DNA replication. The importance of these findings in the treatment of AIDS encephalopathy is discussed.
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PMID:Inhibition of human neurotropic virus (JCV) DNA replication in glial cells by camptothecin. 839 4

Before embarking on experimental therapies for progressive multifocal leukoencephalopathy (PML), the diagnosis needs to be unequivocally established. Improving the underlying immunodeficiency state is the best initial approach to the management of PML. Immunosuppressive therapies should be discontinued when feasible. In the patient with AIDS, highly active antiretroviral therapy should be administered; this appears to prolong survival. At present, no therapy has been demonstrated to be effective in a well-designed prospective trial. Cytosine arabinoside, which has demonstrated efficacy in vitro against JC virus, has not been effective when administered intravenously or intrathecally to patients with AIDS and PML. The failure of regimens employing cytosine arabinoside in PML may have been the consequence of inadequate penetration of the drug to sites of infection in the brain. Other drugs with established in vitro activity against JC virus, such as topoisomerase and camptothecin, are poorly tolerated. The use of cidofovir in patients with AIDS and PML remains anecdotal, although it is currently under investigation. Interferon alfa may improve survival in patients with AIDS and PML and may have general applicability to PML regardless of the cause of the underlying immunodeficient state. Approximately 7% to 9% of patients with PML demonstrate prolonged survival (>12 months) and associated improvement in clinical and radiographic abnormalities in the absence of specific therapy. In patients with AIDS-related PML, prolonged survival correlates with PML as the presenting manifestation of AIDS, higher CD4 T-lymphocyte counts, and contrast enhancement of PML lesions on radiographic imaging. A brisk inflammatory response may also be associated with improved survival. The increased understanding of the pathophysiology of JC virus provides hope for the development of curative strategies. The growing number of persons affected with PML has allowed the organization of carefully designed therapeutic trials to address this issue.
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PMID:Progressive Multifocal Leukoencephalopathy. 1109 61

MLL rearrangements in acute myeloid leukemia (AML) include translocations and intragenic abnormalities such as internal duplication and breakage induced by topoisomerase II inhibitors. In adult AML, FLT3 internal tandem duplications (ITDs) are more common in cases with MLL intragenic abnormalities (33%) than those with MLL translocation (8%). Mutation/deletion involving FLT3 D835 are found in more than 20% of cases with MLL intragenic abnormalities compared with 10% of AML with MLL translocation and 5% of adult AML with normal MLL status. Real-time quantification of FLT3 in 141 cases of AML showed that all cases with FLT3 D835 express high level transcripts, whereas FLT3-ITD AML can be divided into cases with high-level FLT3 expression, which belong essentially to the monocytic lineage, and those with relatively low-level expression, which predominantly demonstrate PML-RARA and DEK-CAN. FLT3 abnormalities in CBF leukemias with AML1-ETO or CBFbeta-MYH11 were virtually restricted to cases with variant CBFbeta-MYH11 fusion transcripts and/or atypical morphology. These data suggest that the FLT3 and MLL loci demonstrate similar susceptibility to agents that modify chromatin configuration, including topoisomerase II inhibitors and abnormalities involving PML and DEK, with consequent errors in DNA repair. Variant CBFbeta-MYH11 fusions and bcr3 PML-RARA may also be initiated by similar mechanisms.
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PMID:FLT3 and MLL intragenic abnormalities in AML reflect a common category of genotoxic stress. 1279 58

Of the several kinds of therapy-related leukemia, therapy-related acute promyelocytic leukemia (t-APL) is most closely associated with topoisomerase II inhibitor administration for treatment of malignancies in adults. Although rare in children, the majority of therapy-related malignancies have been etoposide-related APL associated with Langerhans cell histiocytosis. The authors describe the development of t-APL after chemotherapy administered for non-Hodgkin's lymphoma (NHL) in an 8-year-old girl. One month after cessation of the 3-year chemotherapy regimen of doxorubicin and other agents but not etoposide or radiotherapy, the patient was diagnosed with t-APL with positive PML-RARA molecular abnormality. The patient attained a complete remission following treatment with all-trans retinoic acid-containing chemotherapy. Thereafter, she successfully received hematopoietic stem cell transplantation from an HLA-matched sibling donor. Development of t-APL associated with NHL in children appears to be rare.
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PMID:Secondary acute promyelocytic leukemia following chemotherapy for non-Hodgkin's lymphoma in a child. 1521 16

Recurring chromosome abnormalities are strongly associated with certain subtypes of leukemia, lymphoma and sarcomas. More recently, their potential involvement in carcinomas, i.e. prostate cancer, has been recognized. They are among the most important factors in determining disease prognosis, and in many cases, identification of these chromosome abnormalities is crucial in selecting appropriate treatment protocols. Chromosome translocations are frequently observed in both de novo and therapy-related acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). The mechanisms that result in such chromosome translocations in leukemia and other cancers are largely unknown. Genomic breakpoints in all the common chromosome translocations in leukemia, including t(4;11), t(9;11), t(8;21), inv(16), t(15;17), t(12;21), t(1;19) and t(9;22), have been cloned. Genomic breakpoints tend to cluster in certain intronic regions of the relevant genes including MLL, AF4, AF9, AML1, ETO, CBFB, MYHI1, PML, RARA, TEL, E2A, PBX1, BCR and ABL. However, whereas the genomic breakpoints in MLL tend to cluster in the 5' portion of the 8.3 kb breakpoint cluster region (BCR) in de novo and adult patients and in the 3' portion in infant leukemia patients and t-AML patients, those in both the AML1 and ETO genes occur in the same clustered regions in both de novo and t-AML patients. These differences may reflect differences in the mechanisms involved in the formation of the translocations. Specific chromatin structural elements, such as in vivo topoisomerase II (topo II) cleavage sites, DNase I hypersensitive sites and scaffold attachment regions (SARs) have been mapped in the breakpoint regions of the relevant genes. Strong in vivo topo II cleavage sites and DNase I hypersensitive sites often co-localize with each other and also with many of the BCRs in most of these genes, whereas SARs are associated with BCRs in MLL, AF4, AF9, AML1, ETO and ABL, but not in the BCR gene. In addition, the BCRs in MLL, AML1 and ETO have the lowest free energy level for unwinding double strand DNA. Virtually all chromosome translocations in leukemia that have been analyzed to date show no consistent homologous sequences at the breakpoints, whereas a strong non-homologous end joining (NHEJ) repair signature exists at all of these chromosome translocation breakpoint junctions; this includes small deletions and duplications in each breakpoint, and micro-homologies and non-template insertions at genomic junctions of each chromosome translocation. Surprisingly, the size of these deletions and duplications in the same translocation is much larger in de novo leukemia than in therapy-related leukemia. We propose a non-homologous chromosome recombination model as one of the mechanisms that results in chromosome translocations in leukemia. The topo II cleavage sites at open chromatin regions (DNase I hypersensitive sites), SARs or the regions with low energy level are vulnerable to certain genotoxic or other agents and become the initial breakage sites, which are followed by an excision end joining repair process.
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PMID:Chromatin structural elements and chromosomal translocations in leukemia. 1689 85

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 acute promyelocytic leukemia (t-APL) with t(15;17) translocation is a well-recognized complication of cancer treatment with agents targeting topoisomerase II. However, cases are emerging after mitoxantrone therapy for multiple sclerosis (MS). Analysis of 12 cases of mitoxantrone-related t-APL in MS patients revealed an altered distribution of chromosome 15 breakpoints versus de novo APL, biased toward disruption within PML intron 6 (11 of 12, 92% vs 622 of 1022, 61%: P = .035). Despite this intron spanning approximately 1 kb, breakpoints in 5 mitoxantrone-treated patients fell within an 8-bp region (1482-9) corresponding to the "hotspot" previously reported in t-APL, complicating mitoxantrone-containing breast cancer therapy. Another shared breakpoint was identified within the approximately 17-kb RARA intron 2 involving 2 t-APL cases arising after mitoxantrone treatment for MS and breast cancer, respectively. Analysis of PML and RARA genomic breakpoints in functional assays in 4 cases, including the shared RARA intron 2 breakpoint at 14 446-49, confirmed each to be preferential sites of topoisomerase IIalpha-mediated DNA cleavage in the presence of mitoxantrone. This study further supports the presence of preferential sites of DNA damage induced by mitoxantrone in PML and RARA genes that may underlie the propensity to develop this subtype of leukemia after exposure to this agent.
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PMID:Molecular analysis of t(15;17) genomic breakpoints in secondary acute promyelocytic leukemia arising after treatment of multiple sclerosis. 1865 Apr 49

The translocation t(16;21) involving RUNX1 (AML1) and resulting in the RUNX1-CBFA2T3 fusion is a rare but recurrent abnormality mostly found in therapy-related acute myeloid leukemia (t-AML) associated with agents targeting topoisomerase II (topo II). We characterized, at the genomic level, the t(16;21) translocation in a patient who developed t-AML after treatment of multiple sclerosis with mitoxantrone (MTZ). Long template nested PCR of genomic DNA followed by direct sequencing enabled the localization of RUNX1 and CBFA2T3 (ETO2) breakpoints in introns 5 and 3, respectively. Sequencing of the cDNA with specific primers showed the presence of the expected RUNX1-CBFA2T3 fusion transcript in leukemic cells. The RUNX1 intron 5 breakpoint was located at nucleotide position 24,785. This region contained an ATGCCCCAG nucleotide sequence showing approximately 90% homology to a "hotspot" DNA region ATGCCCTAG present in intron 6 of PML previously identified in therapy-related acute promyelocytic leukemia cases arising following treatment with MTZ. This study suggests a wider distribution in the human genome, and particularly at genes involved in chromosome translocations observed in t-AML, of DNA regions (hotspot) targeted by specific topo II drugs.
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PMID:Identification of a potential "hotspot" DNA region in the RUNX1 gene targeted by mitoxantrone in therapy-related acute myeloid leukemia with t(16;21) translocation. 1902 77


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