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)

Balanced chromosome rearrangements are the hallmark of therapy-related leukemia that develops in patients treated with topoisomerase II inhibitors. Many of these rearrangements involve recurrent chromosomal sites and associated genes (11q23/MLL, 21q22.3/AML1, and 11p15/NUP98), which can interact with a variety of partner genes. One such rearrangement is the rare t(1;11)(q23;p15), which involves juxtaposition of the homeobox gene PMX1 (PRRX1) and NUP98. We report on an additional patient with t(1;11) who presented with myelodysplastic syndrome (MDS) subsequent to treatment for a pleomorphic liposarcoma. With time, the patient's disorder progressed to acute myelomonocytic leukemia with cytogenetic evidence of clonal evolution. To our knowledge, this is the first report of a patient presenting with a myelodysplastic syndrome with isolated t(1;11) (q23;p15), which evolved into therapy-related acute myeloid leukemia (t-AML). This patient is the third reported with this cytogenetic rearrangement and t-AML, and is compared with the other two reports of t(1;11)(q23;p15).
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PMID:Rare t(1;11)(q23;p15) in therapy-related myelodysplastic syndrome evolving into acute myelomonocytic leukemia: a case report and review of the literature. 1788 7

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

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

One of the MLL fusion partners in leukemia is the SEPT6 gene, which belongs to the evolutionarily conserved family of genes of septins. In this work we aimed to characterize at both the RNA and DNA levels three acute myeloid leukemias with cytogenetic evidence of a rearrangement between 11q23 and Xq24. Molecular analysis led to the identification of several MLL-SEPT6 fusion transcripts in all cases, including a novel MLL-SEPT6 rearrangement (MLL exon 6 fused with SEPT6 exon 2). Genomic DNA breakpoints were found inside or near Alu or LINE repeats in the MLL breakpoint cluster region, whereas the breakpoint junctions in the SEPT6 intron 1 mapped to the vicinity of GC-rich low-complexity repeats, Alu repeats, and a topoisomerase II consensus cleavage site. These data suggest that a non-homologous end-joining repair mechanism may be involved in the generation of MLL-SEPT6 rearrangements in acute myeloid leukemia.
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PMID:Molecular characterization of the MLL-SEPT6 fusion gene in acute myeloid leukemia: identification of novel fusion transcripts and cloning of genomic breakpoint junctions. 1849 91

Therapy-related acute myeloid leukemia (t-AML) caused by MLL rearrangements (rMLL) can arise from topoisomerase II agents. However, whether rMLL-related leukemogenesis is inextricably linked to drug cytotoxicity remains controversial. We therefore compared (i) rMLL in children with acute lymphoblastic leukemia (ALL) who developed t-AML and those who did not, (ii) epipodophyllotoxin toxicity in patients with t-AML and in controls, and (iii) rMLL in cells sensitive to etoposide and in those resistant to etoposide. In children with ALL, rMLL appeared to be more frequent in children who developed t-AML than in those who did not (seven pairs, P = 0.04), although independent of the cumulative etoposide dose (P = 0.5). Similarly, the frequency of epipodophyllotoxin-related toxicities did not differ between patients with t-AML and controls (26 pairs, P > 0.17). Moreover, in 25 cell lines, etoposide-induced MLL fusions did not differ in sensitive vs. resistant lines at equitoxic concentrations (P = 0.65). Together, these results indicate that epipodophyllotoxin-mediated leukemogenesis is not directly linked to drug cytotoxicity.
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PMID:Etoposide sensitivity does not predict MLL rearrangements or risk of therapy-related acute myeloid leukemia. 1850 29

The successful treatment of paediatric malignancies by multimodal therapy has improved outcomes for children with cancer, especially those with acute lymphoblastic leukaemia (ALL). Second malignant neoplasms, however, represent a serious complication after treatment. Depending on dosage, 2-12% of patients treated with topoisomerase II inhibitors and/or alkylating agents develop treatment-related acute myeloid leukaemia characterized by translocations at 11q23. Our goal was to study MLL rearrangements in peripheral lymphocytes using cytogenetic and molecular methods in order to evaluate the late effects of cancer therapy in patients previously treated for childhood ALL. Chromosomal rearrangements at 11q23 were analysed in cytogenetic preparations from 49 long-term ALL survivors and 49 control individuals. Patients were subdivided depending on the inclusion or omission of topoisomerase II inhibitors (VP-16 and/or VM-26) in their treatment protocol. The statistical analysis showed significant (P = 0.007) differences between the frequency of translocations observed for the groups of patients and controls. These differences were also significant (P = 0.006) when the groups of patients (independent of the inclusion of topoisomerase II inhibitors) and controls were compared (P = 0.006). The frequencies of extra signals, however, did not differ between groups of patients and controls. Several MLL translocations were detected and identified by inverse polymerase chain reaction, followed by cloning and sequencing. Thirty-five patients (81%) presented putative translocations; among those, 91% corresponded with t(4;11) (q21;q23), while the other 9% corresponded with t(11;X), t(8;11)(q23;q23) and t(11;16). Our results indicate an increase in MLL aberrations in childhood ALL survivors years after completion of therapy. The higher frequency in this cohort might be associated with therapy using anti-tumoural drugs, independent of the inclusion of topoisomerase II inhibitors. Even though the biological significance of these rearrangements needs further investigation, they demonstrate a degree of genome instability, indicating the relevance of cytogenetic and molecular studies during the follow-up of patients in complete clinical remission.
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PMID:Cytogenetic and molecular analysis of MLL rearrangements in acute lymphoblastic leukaemia survivors. 1902 82

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

A balanced translocation involving 11q23 (MLL gene) could be observed in therapy related leukemia (TRL) patients generally treated with topoisomerase II inhibitors. Few reports have been published on TRL following docetaxel administration. Herein, we report a patient who developed acute myelomonocytic leukemia (AMMoL) with t (9; 11) (p22; q23) following chemotherapy mainly consisted of docetaxel for advanced prostatic carcinoma. A 69-year-old man was treated with a systemic chemotherapy containing docetaxel (total dose = 585 mg) for hormone-refractory metastatic poorly differentiated prostate carcinoma. Although, no disease progression of the prostatic carcinoma was observed, AMMoL with t (9; 11) (p22; q23) developed only ten months later from the administration of docetaxel. Docetaxel was considered to be the cause of TRL because of the presence of t (9; 11) (p22; q23) translocation and clinical course.
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PMID:[Therapy related leukemia with 11q23 abnormality induced by chemotherapy consisted of docetaxel for advanced prostatic carcinoma: case report]. 1966 46

In the highly active antiretroviral therapy era, an increasingly large number of HIV-infected patients are developing non- AIDS-defining cancers (NADCs). As patients survive longer, long-term therapy-related complications take on greater importance. Herein, we describe a patient with AIDS who presented to medical attention with pancytopenia 48 months postchemotherapy with etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (R-EPOCH) for diffuse large B-cell lymphoma. Bone marrow biopsy showed a moderately hypocellular marrow; 51% of the nucleated cells were blasts with myelomonocytic differentiation. Cytogenetic studies revealed an abnormal karyotype with deletion of the long arm of chromosome 11 (11q21) and 2 additional copies of the MLL gene attached to the short arms of chromosome 10 in 80% of the metaphase cells examined. With the diagnosis of therapy-related acute myeloid leukemia (AML) secured, he began induction chemotherapy with idarubicin and cytarabine. Two weeks later, he died of fungal septicemia and multiorgan failure. Through a literature search, we were able to identify 4 additional cases of therapy-related AML in AIDS patients following chemotherapy for lymphomas. The median age of these patients at the time of AML diagnosis was 39 years (range, 33-59 years), the median time from the treatment of lymphoma to AML was 18 months (range, 11-48 months), and the median survival following induction chemotherapy was 4 weeks (range, 2-16 weeks). With many HIV-infected patients surviving alkylator and topoisomerase inhibitor-based treatment and radiation therapy for AIDS-defining cancers and NADCs, long-term follow-up for therapy-related complications assumes greater importance.
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PMID:Therapy-related acute myeloid leukemia following HIV-associated lymphoma. 1971 83

Therapy-related acute lymphoblastic leukemia (t-ALL) is a rare secondary leukemia following chemotherapy and/or radiotherapy for primary malignancies. Chromosomal 11q23 abnormality, frequently detected in therapy-related acute myeloid leukemia, is the most common cytogenetic alteration in t-ALL. However, t-ALL cases without 11q23 abnormality have been rarely described. We describe 6 adults with secondary t-ALL without 11q23 abnormalities following various treatment regimens for primary malignancies. We also reviewed 48 t-ALL cases, with complete chromosomal karyotyping, reported in the literature from 1992 to 2007. In the 48 cases, an 11q23 abnormality involving the MLL gene locus was the predominant chromosomal aberration (32 [67%]), followed by t(9;22) (6 [13%]) and a normal karyotype (4 [8%]). Compared with t-ALL cases with an 11q23 abnormality, cases without an 11q23 abnormality had a relatively longer latency period (median, 36 vs 19 months) and a different primary malignancy spectrum. No major difference was observed between groups in regard to age, sex, or receipt of a topoisomerase II inhibitor. The t(8;14)(q11.2;q32), a rare, nonrandom, balanced chromosomal translocation differing from the more common translocation involving c-MYC on chromosome 8q24, was seen in 1 adult t-ALL case, which may suggest another possible pathogenesis of this disease.
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PMID:Therapy-related acute lymphoblastic leukemia without 11q23 abnormality: report of six cases and a literature review. 2002 61


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