Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A family of A + T-rich sequences termed MARs ("matrix association regions") mediate chromosomal loop attachment. Here we demonstrate that several MARs both specifically bind and contain multiple sites of cleavage by topoisomerase II, a major protein of the mitotic chromosomal scaffold. Interestingly, "hotspots" of enzyme cutting occur within the MAR of the mouse immunoglobulin kappa-chain gene at the breakpoint of a previously described chromosomal translocation. Since topoisomerase II can mediate illegitimate recombination in prokaryotes, we explored further the possibility that MARs might be targets for this process in eukaryotes. We found that a MAR had been deleted from one of the two rabbit immunoglobulin kappa-chain genes and that MARs reside next to a long interspersed repetitive element within the recombination junction of a human ring chromosome 21. These results, taken together with other accounts of nonhomologous recombination, lead to the proposal that a dysfunction of MARs is illegitimate recombination.
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PMID:Dysfunction of chromosomal loop attachment sites: illegitimate recombination linked to matrix association regions and topoisomerase II. 254 56

Development of myelodysplasia (MDS) with subsequent progression to acute myeloid leukemia (AML) is an example of the multistep process of malignant transformation in which each step often relates to genetic abnormalities that can be directly seen as chromosomal aberrations. Therapy-related MDS and AML (t-MDS and t-AML) may serve as an ideal model for a study of the genetic evolution of MDS and AML because chromosomal abnormalities are observed in most cases and because the disease is often diagnosed early due to a close patient follow-up. The cytogenetic characteristics at diagnosis were studied in 137 consecutive cases of t-MDS and t-AML, including 22 new cases, and correlated with the clinical characteristics and the course of the disease. Balanced translocations to chromosome bands 11q23 and 21q22 represent primary steps in pathways leading directly to overt t-AML. Specific chromosomal deletions or losses, on the other hand, represent primary or secondary events in alternative pathways leading to t-MDS with potential for subsequent transformation to overt t-AML. Loss of a whole chromosome 7 (-7) or deletion of its long arm (7q-) and deletion of the long arm of a chromosome 5 (5q-) were the most frequent primary abnormalities significantly related to t-MDS. Loss of a whole chromosome 5 (-5) was also a primary event, but surprisingly, was observed equally in t-MDS and in t-AML. Deletion of chromosome 13, including bands q13q14, was another less common primary aberration of t-MDS. Except for -7 and del(13q), these primary aberrations were most often observed together with secondary abnormalities. These included balanced aberrations involving band 3q26 and various deletions of chromosome 3, a gain of a whole chromosome 8, deletions of the short arm or loss of chromosomes 12 and 17, loss of a whole chromosome 18, and deletions of the short arm of chromosome 21. Deletions or loss or chromosomes 5 and 7 were significantly associated with previous therapy with alkylating agents (P = .002), and balanced translocations to chromosome bands 3q26, 11q23, and 21q22 were significantly associated with previous therapy with drugs targeting DNA-topoisomerase II (P < .00005). Other characteristic aberrations were not related to any specific type of therapy. The molecular changes believed to contribute to the development of t-MDS and t-AML have been identified for many of these chromosomal abnormalities.
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PMID:Different genetic pathways in leukemogenesis for patients presenting with therapy-related myelodysplasia and therapy-related acute myeloid leukemia. 757 62

AML1 is involved at the breakpoint of chromosome 21 band q22 in several recurring chromosomal translocations associated with myeloid and lymphoid leukemias. AML1 corresponds to CBFA2, and encodes one of the DNA-binding subunits of the enhancer core binding factor CBF. Other members of this family of DNA-binding proteins are CBFA1 and CBFA3, also known as AML3 and AML2. The three proteins are characterized by a highly conserved domain (runt domain, > 90% homology) at the amino end that is necessary for DNA-binding and protein dimerization, and by a unique domain at the carboxyl end that is necessary for transactivation. Two recurring chromosomal translocations involving AML1 associated with myeloid leukemias are the t(8;21)(q22;q22), seen in 20% of patients with acute myeloid leukemia (AML) M2, and the t(3;21)(q26;q22), that occurs in myeloid leukemias primarily following treatment with topoisomerase II inhibitors. In five patients with a t(3;21) whom we studied, AML1 is interrupted by the translocation breakpoint between the runt domain and the transactivation domain, and is fused to two genes on chromosome band 3q26: EAP, which encodes the ribosomal protein L22, and MDS1, which encodes a small polypeptide of unknown function. In one of the five patients we studied, a fusion with a third gene EVI1 also occurs. The fusion of EAP to AML1 is not in frame, and leads to a protein that is terminated shortly after the fusion junction by introduction of a stop codon. The fusion of AML1 to MDS1 is in frame, and adds 127 codons to the interrupted AML1. Thus, in the five cases that we studied, the 3;21 translocation results in expression of two coexisting chimeric mRNAs which contain the identical runt domain at the 5' region, but differ in the 3' region. In addition, the chimeric junction AML1/MDS1/EVII has been detected in cells from one of our patients with the 3;21 translocation. Several genes necessary for myeloid lineage differentiation contain the target sequence for AML1 in their regulatory regions. We have compared the normal AML1 to AML1/MDS1 and AML1/EAP as transcriptional regulators of the CSF1R promoter which contains the CBF target sequence. Our results indicate that whereas the normal AML1 can activate the promoter, the chimeric proteins compete with the normal AML1 and repress expression from the CSF1R promoter. To determine the role of the chimeric proteins in cell growth, we expressed their cDNA in rat fibroblasts. When either fusion gene is expressed, the cells lose contact inhibition and form foci over the monolayer. However, only cells expressing AML1/MDS1 grow as large tumors in nude mice. Thus, although both chimeric genes have similar effects in transactivation of the CSF1R promoter, they affect cell growth as tumor promoters differently in vivo.
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PMID:Rearrangements of the AML1/CBFA2 gene in myeloid leukemia with the 3;21 translocation: in vitro and in vivo studies. 920 63

A 59-year-old female suffering from malignant lymphoma developed therapy-related acute myeloblastic leukemia (t-AML) after chemotherapy consisting of treatment with DNA-topoisomerase II inhibitors, etoposide and mitoxantrone, and an alkylating agent, cyclophosphamide. The cumulative dose of etoposide administration was 5500 mg; 1500 mg given intravenously and 4000 mg orally. One year later, she suddenly developed AML of FAB M2. Cytogenetic analysis of bone marrow cells revealed deletion of 7q and a rare translocation, t(16;21)(q24;q22). Southern blot analysis of bone marrow cells did not detect rearrangement of the AML1 gene, however, fluorescence in situ hybridization (FISH) analysis of bone marrow cells at interphase and metaphase revealed a translocational splitting between chromosome 21 involving AML1 gene and chromosome 16. These results suggest that the breakpoint is not located in the breakpoint cluster region for t(8;21). The patient was treated with chemotherapy and entered complete remission.
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PMID:A case of therapy-related acute myeloblastic leukemia with t(16;21)(q24;q22) after chemotherapy with DNA-topoisomerase II inhibitors, etoposide and mitoxantrone, and the alkylating agent, cyclophosphamide. 963 85

The t(3;21)(q26;q22) is a recurring chromosomal abnormality in blastic crisis of chronic myelogenous leukemia (CML) and in therapy-related myelodysplastic syndrome and acute leukemia. In order to clarify the genetic recombination mechanism underlying the t(3;21), we molecularly cloned the breakpoints and determined their nucleotide sequence in a case of CML in blastic crisis with t(3;21). Near the breakpoint on chromosome 21, three homopyrimidine (CT)-rich sequences were found. We also identified a sequence homologous to the topoisomerase II binding and cleavage consensus sequence surrounding the breakpoint on chromosome 3, and two topoisomerase II binding and cleavage consensus sequences near the breakpoint on chromosome 21. In addition, around the breakpoint on chromosome 21, four chi-like sequences, potential consensus signals for activating recombination, were found. There were no Alu sequences or antigen receptor gene-like heptamer/nonamer signal sequences within the breakpoints on chromosomes 3 and 21. The breakpoints were found adjacent to the topoisomerase II binding and cleavage consensus sequence or the homopyrimidine-rich sequence. Furthermore, the chi-like sequences and the homopyrimidine-rich sequence were detected on chromosome 21 but not on chromosome 3. Genes Chromosomes Cancer 26:92-96, 1999.
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PMID:Molecular characterization of the genomic breakpoints in a case of t(3;21)(q26;q22). 1044 Oct 11