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)

Several recurring chromosomal translocations involve the AML1 gene at 21q22 in myeloid leukemias resulting in fusion mRNAs and chimeric proteins between AML1 and a gene on the partner chromosome. AML1 corresponds to CBFA2, one of the DNA-binding subunits of the enhancer core binding factor CBF. Other CBF DNA-binding subunits are CBFA1 and CBFA3, also known as AML3 and AML2. AML1, AML2 and AML3 are each characterized by a conserved domain at the amino end, the runt domain, that is necessary for DNA-binding and protein dimerization, and by a transactivation domain at the carboxyl end. AML1 was first identified as the gene located at the breakpoint junction of the 8;21 translocation associated with acute myeloid leukemia. The t(8;21)(q22;q22) interrupts AML1 after the runt homology domain, and fuses the 5' part of AML1 to almost all of ETO, the partner gene on chromosome 8. AML1 is an activator of several myeloid promoters; however, the chimeric AML1/ETO is a strong repressor of some AML1-dependent promoters. AML1 is also involved in the t(3;21)(q26;q22), that occurs in myeloid leukemias primarily following treatment with topoisomerase II inhibitors. We have studied five patients with a 3;21 translocation. In all cases, AML1 is interrupted after the runt domain, and is translocated to chromosome band 3q26. As a result of the t(3;21), AML1 is consistently fused to two separate genes located at 3q26. The two genes are EAP, which codes for the abundant ribosomal protein L22, and MDS1, which encodes a small polypeptide of unknown function. In one of our patients, a third gene EVI1 is also involved. EAP is the closest to the breakpoint junction with AML1, and EVI1 is the furthest away. 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 transcript AML1/MDS1/EVI1 has also been detected in cells from one patient with the 3;21 translocation as well as in one of our patients. Several genes necessary for myeloid lineage differentiation contain the target sequence for AML1 in their regulatory regions. One of them is the CSF1R gene. We have compared the normal AML1 to AML1/MDS1, AML1/EAP and AML1/MDS1/EVI1 as transcriptional regulators of the CSF1R promoter. Our results indicate that AML1 can activate the promoter, and that the chimeric proteins compete with the normal AML1 and repress expression from the CSF1R promoter. AML1/MDS1 and AML1/EAP affect cell growth and phenotype when expressed in rat fibroblasts. However, the pattern of tumor growth of cells expressing the different chimeric genes in nude mice is different. We show that when either fusion gene is expressed, the cells lose contact inhibition and form foci over the monolayer. In addition, cells expressing AML1/MDS1 grow larger tumors in nude mice, whereas cells expressing only AML1/EAP do not form tumors, and cells expressing both chimeric genes induce tumors of intermediate size. Thus, although both chimeric genes have similar effects in transactivation assays of the CSF1R promoter, they affect cell growth differently in culture and have opposite effects as tumor promoters in vivo. Because of the results obtained with cells expressing one or both genes, we conclude that MDS1 seems to have tumorigenic properties, but that AML1/EAP seems to repress the oncogenic property of AML1/MDS1.
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PMID:Rearrangement of the AML1/CBFA2 gene in myeloid leukemia with the 3;21 translocation: expression of co-existing multiple chimeric genes with similar functions as transcriptional repressors, but with opposite tumorigenic properties. 858 55

Treatment-related acute myeloid leukemia (t-AML) following successful therapy of a primary malignancy has been recognized with increasing frequency among cancer survivors over the past several years. Many of these t-AML cases are associated with the use of intensive chemotherapy regimens that employ one or more agents which target eukaryotic topoisomerase II (topo II), and demonstrate non-random chromosomal translocations involving either the MLL (ALL-1, HRX) gene at 11q23 or the AML1 gene at 21q22. Although many investigators have speculated that these translocations are induced by the therapeutic use of topo II inhibitors, the molecular sequence of events by which topo II inhibitors might induce a chromosomal translocation are not well understood. We describe here the reproducible induction of highly specific, double-strand DNA cleavage at a specific site within the AML1 locus by topo II inhibitors. This DNA cleavage, which maps to a region of the AML1 locus frequently disrupted by chromosomal translocations, can be induced in several cell lines, with multiple different topo II inhibitors, indicating that this phenomenon is not restricted to a specific cell type or specific topo II inhibitor. It is conceivable that site-specific double-strand DNA cleavage within the AML1 locus induced by topo II inhibitors represents the initial molecular event leading to a chromosomal translocation and t-AML.
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PMID:Topoisomerase II inhibitors induce DNA double-strand breaks at a specific site within the AML1 locus. 909 88

One of the most serious consequences of cancer therapy is the development of a second cancer, especially leukemia. Several distinct subsets of therapy-related leukemia can now be distinguished. Classic therapy-related myeloid leukemia typically occurs 5 to 7 years after exposure to alkylating agents and/or irradiation, has a myelodysplastic phase with trilineage involvement, and is characterized by abnormalities of the long arms of chromosomes 5 and/or 7. Response to treatment is poor, and allogenic bone marrow transplantation is recommended. Leukemia following treatment with agents that inhibit topoisomerase II, however, has a shorter latency, no preleukemic phase, a monoblastic, myelomonocytic, or myeloblastic phenotype, and balanced translocations, most commonly involving chromosome bands 11q23 or 21q22. The MLL gene at 11q23 or the AML1 gene at 21q22 are almost uniformly rearranged. MLL is involved with many fusion gene partners. Therapy-related acute lymphoblastic leukemia also occurs with 11q23 rearrangements. Therapy-related leukemias with 11q23 or 21q22 rearrangements, inv(16) or t(15;17), have a more favorable response to treatment and a clinical course similar to their de novo counterparts.
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PMID:Myeloid leukemia after hematotoxins. 911 10

A distinct population of therapy-related acute myeloid leukemia (t-AML) is strongly associated with prior administration of topoisomerase II (topo II) inhibitors. These t-AMLs display distinct cytogenetic alterations, most often disrupting the MLL gene on chromosome 11q23 within a breakpoint cluster region (bcr) of 8.3 kb. We recently identified a unique site within the MLL bcr that is highly susceptible to DNA double-strand cleavage by classic topo II inhibitors (e.g., etoposide and doxorubicin). Here, we report that site-specific cleavage within the MLL bcr can be induced by either catalytic topo II inhibitors, genotoxic chemotherapeutic agents which do not target topo II, or nongenotoxic stimuli of apoptotic cell death, suggesting that this site-specific cleavage is part of a generalized cellular response to an apoptotic stimulus. We also show that site-specific cleavage within the MLL bcr can be linked to the higher-order chromatin fragmentation that occurs during the initial stages of apoptosis, possibly through cleavage of DNA loops at their anchorage sites to the nuclear matrix. In addition, we show that site-specific cleavage is conserved between species, as specific DNA cleavage can also be demonstrated within the murine MLL locus. Lastly, site-specific cleavage during apoptosis can also be identified at the AML1 locus, a locus which is also frequently involved in chromosomal rearrangements present in t-AML patients. In conclusion, these results suggest the potential involvement of higher-order chromatin fragmentation which occurs as a part of a generalized apoptotic response in a mechanism leading to chromosomal translocation of the MLL and AML1 genes and subsequent t-AML.
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PMID:DNA cleavage within the MLL breakpoint cluster region is a specific event which occurs as part of higher-order chromatin fragmentation during the initial stages of apoptosis. 919 42

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

CBFA2(AML1) has emerged as a gene critical in hematopoiesis; its protein product forms the DNA-binding subunit of the heterodimeric core-binding factor (CBF) that binds to the transcriptional regulatory regions of genes, some of which are active specifically in hematopoiesis. CBFA2 forms a fusion gene with ETO and MDS1/EVI1 in translocations in myeloid leukemia and with ETV6(TEL) in the t(12;21) common in childhood pre-B acute lymphoblastic leukemia. We have analyzed samples from 30 leukemia patients who had chromosome rearrangements involving 21q22 by using fluorescence in situ hybridization (FISH). Our analysis showed that 7 of them involved CBFA2 and new translocation partners. Two patients had a t(17;21)(q11.2;q22), whereas the other 5 had translocations involving 1p36, 5q13, 12q24, 14q22, or 15q22. Five of these novel breakpoints in CBFA2 occurred in intron 6; this same intron is involved in the t(3;21). One breakpoint mapped to the t(8;21) breakpoint region in intron 5, and 1 mapped 5' to that region. All 7 CBFA2 rearrangements resulted from balanced translocations. All 7 patients had myeloid disorders (acute myeloid leukemia or myelodysplastic syndrome); 2 were de novo and 5 had treatment histories that included topoisomerase II targeting agents. The association of therapy-related disorders with translocations involving CBFA2 was significant by Fisher's exact test (P < .003). These results provide further evidence that this region of CBFA2 is susceptible to breakage in cells exposed to topoisomerase II inhibitors.
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PMID:CBFA2(AML1) translocations with novel partner chromosomes in myeloid leukemias: association with prior therapy. 976 73

Phenotypic conversion from acute myeloid leukemia (AML) to acute lymphoblastic leukemia (ALL) is rare. A 38-year-old man was initially diagnosed as having AML (FAB-M2) associated with the t(8;21)(q22;q22) chromosomal abnormality. The blasts showed myeloperoxidase (MPO) activity and CD13 antigen expression. He showed complete remission after standard chemotherapy for AML. However, the patient relapsed with blasts showing ALL morphology (FAB-L1), MPO negativity, and CD19 antigen expression 33 months after cessation of AML therapy. Cytogenetic analysis at relapse was unsuccessful. Molecular analysis of ALL blasts revealed immunoglobulin heavy-chain gene and MLL gene rearrangements but no AML1 gene. MLL gene rearrangement or the 11q23 chromosomal abnormality has been associated with therapy-related leukemia. The subsequent ALL in our patient may have been induced by the chemotherapy including daunorubicin, known as a topoisomerase II inhibitor.
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PMID:Phenotypic conversion from t(8;21) acute myeloid leukemia to MLL gene rearrangement-positive acute lymphoblastic leukemia. 984 25

TEL-AML1 gene fusion derived by chromosomal translocation is a common acquired genetic lesion in pediatric cancer that is present in approximately 25% of B-cell precursor acute lymphoblastic leukemias, and recent evidence suggests that this recombination event may initiate leukemogenesis prenatally during fetal hemopoiesis. Analysis of the DNA sequence and structure surrounding the breakpoints may reveal clues to their formation. A long-distance inverse PCR strategy was used to amplify TEL-AML1 genomic fusion sequences from diagnostic DNA from nine patients. Breakpoints were scattered within the 14 kb of intronic DNA between exons 5 and 6 of TEL and in two putative cluster regions within AML1 intron 1. Fusion sequences exhibited characteristic signs of nonhomologous end joining, including microhomologies at the end points, and small deletions and duplications. DNA sequences near the breakpoints did not reveal any consistent characteristic signal sequences of the V(D)J recombinase, topoisomerase II consensus sites, or other sequence motifs associated with recombination. However, several translocations occurred near a repeat region of TEL that was found to be highly polymorphic. This region was cloned and found in nuclease sensitivity assays to exhibit paranemic structures, which may have contributed to DNA breakage or illegitimate recombination. The data are compatible with the possibility that TEL-AML1 translocations occur by nonhomologous recombination involving imprecise, constitutive repair processes following DNA double-strand breaks.
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PMID:Structure and possible mechanisms of TEL-AML1 gene fusions in childhood acute lymphoblastic leukemia. 1046 10

Rearrangements and fusion of the MLL gene with various alternative partner genes occur in approximately 80% of infant leukemias and are acquired during fetal hemopoiesis in utero. Similar MLL gene recombinants also occur in topoisomerase II-inhibiting drug-induced leukemias. These data have led to the suggestion that some infant leukemia may arise via transplacental fetal exposures during pregnancy to substances that form cleavable complexes with topoisomerase II and induce illegitimate recombination of the MLL gene. A structural feature shared by many topoisomerase II-inhibiting drugs and other chemicals is the quinone moiety. We assayed, by PCR-RFLP, for a polymorphism in an enzyme that detoxifies quinones, NAD(P)H:quinone oxidoreductase (NQO1), in a series (n = 36) of infant leukemias with MLL rearrangements versus unselected cord blood controls (n = 100). MLL-rearranged leukemias were more likely to have genotypes with low NQO1 function (heterozygous CT or homozygous TT at nucleotide 609) than controls (odds ratio, 2.5; P = 0.015). In contrast, no significant allele bias was seen in other groups of pediatric leukemias with TEL-AML1 fusions (n = 50) or hyperdiploidy (n = 29). In the subset of infant leukemias that had MLL-AF4 fusion genes (n = 21), the bias increase in low or null function NQO1 genotypes was more pronounced (odds ratio, 8.12; P = 0.00013). These data support the idea of a novel causal mechanism in infant leukemia involving genotoxic exposure in utero and modulation of impact on a selective target gene by an inherited allele encoding a rate-limiting step in a carcinogen detoxification pathway.
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PMID:A lack of a functional NAD(P)H:quinone oxidoreductase allele is selectively associated with pediatric leukemias that have MLL fusions. United Kingdom Childhood Cancer Study Investigators. 1046 13


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