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

---

Query: EC:5.99.1.3 (topoisomerase)
9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chromosomal aberrations are frequently associated with therapy-related myelodysplastic syndromes and acute myelogenous leukemia (t-MDS/AML) and are thought to result from exposure to genotoxic drugs, including alkylating agents and DNA topoisomerase II poisons. The NUP98 gene on chromosome band 11p15 is involved in several different chromosomal aberrations that have been associated with t-MDS/AML. We have cloned the translocation breakpoints from two cases of t-MDS harboring a t(11;20)(p15;q11). Sequence analysis of the breakpoints from both cases revealed almost perfectly balanced translocations between NUP98 and TOP1. There were no known recombinogenic sequences identified at or near the breakpoints. However, four bp microduplications present at the translocation crossover points suggested that these translocations may have been initiated by 4 bp staggered double-stranded DNA breaks, which are known to be associated with the action of topoisomerase II. Given the history of patient exposure to topoisomerase II poisons, and the fact that these drugs stabilize staggered breaks with a 4 bp overhang, it seems possible that drug-induced topoisomerase II cleavage and subunit exchange was involved in these translocations. These results suggest that NUP98 is a recurrent target for therapy-related malignancies induced by multiagent chemotherapy, and suggest a role for DNA topoisomerase II poisons in the generation of these translocations. Published 2000 Wiley-Liss, Inc.
...
PMID:Potential role for DNA topoisomerase II poisons in the generation of t(11;20)(p15;q11) translocations. 1095 88

Chemotherapy of secondary leukemias is currently still considered to be associated with poor results. However, recent data suggest that the response to remission induction may substantially differ according to the previous medical history of the patients. Therapy related leukemia, arising following exposure to previous alkylating agents or radiotherapy, is often associated with chromosomal abnormalities involving chromosomes 5 and 7 and has a particularly bad response, whereas AML after exposure to epipodophyllotoxins or topoisomerase-II active agents could have a somewhat better response. Acute promyelocytic leukemia secondary to treatment of a primary malignant neoplasm seems to be associated with a better response if compared to other cytotypes of AML or to AML arising after transformation of myelodysplasia. However, here the literature data are not in full agreement, as different kinds of approaches have been applied. In fact, even if the problems encountered in treating patients with secondary leukemia are similar to those seen in patients with AML arising in a background of myelodysplasia (resistant disease and prolonged cytopenia after treatment), there are data suggesting that the use of high dose ara-C, with or without fludarabine, can circumvent resistance in a small but significant number of cases. One of the unsolved problems which still remains is how to consolidate the CR induced with high dose ara-C or with cycles based on anthracycline derivatives. In addition, another question relates to the categories of patients in whom chemotherapy may change the expected survival. Intensive post-remission chemotherapy, with or without autologous HSCT, may constitute an appropriate alternative for patients lacking a suitable sibling donor or for older patients who are in remission after chemotherapy and also able to tolerate other cycles of intensive chemotherapy. In this respect, the specific cytogenetic abnormality involved should be considered the most important prognostic factor for response and disease free survival; patients with abnormalities of chromosome 5 and 7 have a particularly low possibility of response and duration of CR. Furthermore, it is still debatable whether patients, especially the elderly, with these characteristics should go through a series of conventional treatments or just receive supportive treatment. On the other hand, patients with better prognostic factors should be entitled to further intensive treatments, taking into account possible delayed recovery and/or possible less successful collection of peripheral or marrow stem cells.
...
PMID:Chemotherapy of secondary leukemias. 1104 14

Therapy-related MDS and AML are complications of intensive chemotherapy regimens. Traditionally, patients exposed to topoisomerase II inhibitors are reported to develop secondary AML with abnormalities of chromosome 11q23. We evaluated the long-term hematologic toxicity of topoisomerase II-intensive high-dose mitoxantrone-based chemotherapy in 163 newly diagnosed acute leukemia patients treated over an 8 year period. Nine (5.5%) patients developed new cytogenetic abnormalities. Four patients developed MDS with progression to AML, three patients developed new abnormalities at the time of relapse, and three patients (including one of the former patients) had changes that were not associated with hematologic disease. The abnormalities most frequently involved chromosomes 7q, 20q, 1q, and 13q. Despite the use of topoisomerase II-intensive treatment, no patient developed an abnormality involving chromosome 11q23. Spontaneous resolution of some changes and prolonged persistence of others in the absence of hematologic disease indicates that some cytogenetic changes are not sufficient to promote leukemogenesis.
...
PMID:Secondary acute myelogenous leukemia and myelodysplasia without abnormalities of chromosome 11q23 following treatment of acute leukemia with topoisomerase II-based chemotherapy. 1141 84

The mixed lineage leukemia, MLL, gene is frequently rearranged in patients with secondary leukemia following treatment with DNA topoisomerase II inhibitors. By FISH and Southern blot analyses we identified a rearrangement in the MLL gene due to a novel t(3;11)(q28;q23) chromosomal translocation in a patient who developed AML-M5 3 years after treatment for a follicular lymphoma. Through inverse PCR, the LPP (lipoma preferred partner) gene on 3q28 was identified as the MLL fusion partner. LPP contains substantial identity to the focal adhesion protein, zyxin, and is frequently fused to HMGIC in lipomas. The breakpoint occurred in intron 8 of MLL and LPP. Two in-frame MLL-LPP transcripts, which fuse MLL exon 8 to LPP exon 9, were detected by RT-PCR, although the smaller of these contained a deletion of 120 bp from the MLL sequence. The predicted MLL-LPP fusion protein includes the A/T hook motifs and methyltransferase domain of MLL joined to the two last LIM domains of LPP. A reciprocal LPP-MLL transcript, predicted to include the proline-rich and leucine zipper motifs, and the first LIM domain of LPP were also detected by RT-PCR. In summary, LPP is a newly identified MLL fusion partner in secondary leukemia resulting from topoisomerase inhibitors. The MLL-LPP and LPP-MLL predicted proteins contain many of the features present in other MLL rearrangements.
...
PMID:Human LPP gene is fused to MLL in a secondary acute leukemia with a t(3;11) (q28;q23). 1143 29

Therapy-related acute myeloid leukemias (t-AML) with translocations of the MLL gene are associated with the use of topoisomerase II inhibitors. We established the emergence of the malignant clone in a child who developed t-AML with a t(11;19) (q23;p13.3) during treatment for acute lymphoblastic leukemia (ALL). The MLL-ENL and the reciprocal ENL-MLL genomic fusions and their chimeric transcripts were characterized from samples collected at the time of t-AML diagnosis. We used PCR with patient-specific genomic primers to establish the emergence of the MLL-ENL fusion in serially obtained DNA samples. The MLL-ENL fusion was not detectable in bone marrow at the time of ALL diagnosis or after 2 months of chemotherapy (frequency <8.3 x 10(-7) cells(-1)). The genomic fusion was first detected in bone marrow after 6 months of treatment at a frequency of one in 4,000 mononuclear bone marrow cells; the frequency was one in 70 cells after 20 months of therapy. At the first detection of MLL-ENL, the only topoisomerase II inhibitors the patient had received were one dose of daunorubicin and two doses of etoposide. The MLL-ENL fusion was not detectable in blood at the time of ALL diagnosis or after 0.7, 2, 8, 10, and 12 months of therapy but was detectable in blood at 16 months (one in 2.3 x 10(4) cells). Recombinogenic Alu sequences bracketed the breakpoints in both fusions. These data indicate that the malignant clone was not present before therapy, arose early during chemotherapy, and was able to proliferate even during exposure to antileukemic therapy.
...
PMID:Molecular emergence of acute myeloid leukemia during treatment for acute lymphoblastic leukemia. 1152 40

The AML1 (CBFA2) gene is the most frequent target of chromosomal rearrangements observed in human acute leukemia. These rearrangements include the commonly reported t(8;21)(q22;q22) or AML1/ETO fusion in AML-M2, the t(3;21)(q26;q22) or AML1 fusion with one of three genes, MDS1, EAP or EVI1, in therapy-related AML and MDS, as well as in blast crisis in CML and the t(12;21)(p13;q22) or TEL/AML1 fusion in B-cell ALL. In addition to the t(3;21), other AML1 translocations have also been reported in therapy-related MDS and AML, particularly after treatment with topoisomerase II inhibitors. AML1 gene rearrangements have also been observed less frequently with numerous other chromosomal partners. Here, we describe a patient with AML-M4 and a previously unreported rearrangement involving the AML1 locus and an unknown locus on the short arm of chromosome 1 at 1p32.
...
PMID:A unique AML1 (CBF2A) rearrangement, t(1;21)(p32;q22), observed in a patient with acute myelomonocytic leukemia. 1156 47

Childhood myeloid leukaemias are a diverse collection of conditions. Although many are also seen in adults, some are peculiar to childhood. In childhood AML, as in adults, cytogenetic abnormalities are associated with specific clinical features and define prognostic groups. In infants under 1 year with AML, the incidence of 11q23 abnormalities is particularly high. The finding of identical 11q23 breakpoints in infant leukaemia as in therapy-related leukaemias suggests a role for in utero exposure to topoisomerase II inhibitors. There are a number of constitutional disorders that predispose children to develop AML, usually with a preceding myelodysplastic phase. Monosomy (or deletion of the long arm) of chromosome 7 is the most frequent chromosome abnormality in the bone marrow of such patients. Abnormalities of chromosome 7 are also common cytogenetic findings in all morphological subgroups of childhood myelodysplasia, either as a primary abnormality or associated with disease progression.
...
PMID:Childhood myeloid leukaemias. 1164 Aug 70

Therapy-related acute myeloid leukemia (t-AML) in most cases develops after chemotherapy of other malignancies and shows characteristic chromosome aberrations. Two general types of t-AML have previously been identified. One type is observed after therapy with alkylating agents and characteristically presents as therapy-related myelodysplasia with deletions or loss of the long arms of chromosomes 5 and 7 or loss of the whole chromosomes. The other type is observed after therapy with topoisomerase II inhibitors and characteristically presents as overt t-AML with recurrent balanced chromosome aberrations. Recent research suggests that these 2 general types of t-AML can now be subdivided into at least 8 genetic pathways with a different etiology and different biologic characteristics.
...
PMID:Genetic pathways in therapy-related myelodysplasia and acute myeloid leukemia. 1187 59

The International Workshop on the relationship between prior therapy and balanced chromosome aberrations in therapy-related myelodysplastic syndromes (t-MDS) and therapy-related acute leukemia (t-AL) identified 79 of 511 (15.5%) patients with balanced 21q22 translocations. Patients were treated for their primary disease, including solid tumors (56%), hematologic malignancy (43%), and juvenile rheumatoid arthritis (single case), by radiation therapy (5 patients), chemotherapy (36 patients), or combined-modality therapy (38 patients). 21q translocations involved common partner chromosomes in 81% of cases: t(8;21) (n = 44; 56%), t(3;21) (n = 16; 20%), and t(16;21) (n = 4; 5%). Translocations involving 15 other partner chromosomes were also documented with involvement of AML1(CBFA2/RUNX1), identifying a total of 23 different 21q22/AML1 translocations. The data analysis was carried out on the basis of five subsets of 21q22 cases, that is, t(8;21) with and without additional aberrations, t(3;21), t(16;21), and other 21q22 translocations. Dysplastic features were present in all 21q22 cases. Therapy-related acute myeloid leukemia (t-AML) at presentation was highest in t(8;21) (82%) and lowest in t(3;21) (37.5%) patients. Cumulative drug dose exposure scores for alkylating agents (AAs) and topoisomerase II inhibitors indicated that t(3;21) patients received the most intensive therapy among the five 21q22 subsets, and the median AA score for patients with secondary chromosome 7 aberrations was double the AA score for the entire 21q22 group. All five patients who received only radiation therapy had t(8;21) t-AML. The median latency and overall survival (OS) for 21q22 patients were 39 and 14 months (mo), compared to 26 and 8 mo for 11q23 patients, 22 and 28 mo for inv(16), 69 and 7 mo for Rare recurring aberrations, and 59 and 7 mo for Unique (nonrecurring) balanced aberration (latency P < or = 0.016 for all pairwise comparisons; OS, P < or = 0.018 for all pairwise comparisons). The percentages of 21q22 patients surviving 1 year, 2 years, and 5 years were 58%, 33%, and 18%, respectively. Noticeable differences were observed in median OS between 21q22 patients (n = 7) receiving transplant (BMT) (31 mo) compared to 21q22 patients who received intensive non-BMT therapy (n = 46) (17 mo); however, this was nonsignificant because of the small sample size (log-rank, P = 0.33). t-MDS/t-AML with balanced 21q22 aberrations was associated with prior exposure to radiation, epipodophyllotoxins, and anthracyclines, dysplastic morphologic features, multiple partner chromosomes, and longer latency periods when compared to 11q23 and inv(16) t-MDS/AML Workshop subgroups. In general, patients could be divided into two prognostic risk groups, those with t(8;21) (median OS, 19 mo) and those without t(8;21) (median OS, 7 mo) leukemia (log-rank, P = 0.0007).
...
PMID:21q22 balanced chromosome aberrations in therapy-related hematopoietic disorders: report from an international workshop. 1192 Dec 72

The Workshop identified 48 unselected patients with therapy-related myelodysplastic syndrome or acute myeloid leukemia (t-MDS/t-AML) and inv(16), and 41 patients with t(15;17) after chemotherapy (CT) and/or radiotherapy (RT) for a malignant or nonmalignant disease. The primary diseases were: breast cancer, 33 patients; lymphomas, 24 patients; various other solid tumors, 30 patients; and nonmalignant diseases, 2 patients. The general type of previous therapy was RT only in 10 patients with an inv(16) and in 12 patients with a t(15;17), alkylating agents plus topoisomerase II inhibitors in 24 patients with an inv(16) and in 18 patients with a t(15;17), topoisomerase II inhibitors only in 5 patients with an inv(16) and in 2 patients with a t(15;17), alkylating agents only in 6 patients in each subgroup, and other types of chemotherapy in 3 patients in each subgroup. Most CT-treated patients (69%) also received RT. The latency period to development of t-MDS/t-AML was short: a median of 22 months in patients with inv(16) and 29 months in patients with t(15;17). Twenty-six patients (54%) with an inv(16) and 17 patients (41%) with a t(15;17) had additional cytogenetic abnormalities, which were unrelated to age and survival in both subgroups. Trisomy of chromosomes 8, 21, and 22 and del(7q) were the most frequent additional abnormalities in the inv(16) subgroup, whereas +8, -5, and del(16q) were most frequent in the t(15;17) subgroup. The disease was overt t-AML in 38/48 patients (79%) with an inv(16) and in 38/41 patients (93%) with a t(15;17). Thirty-three of 39 intensively treated patients (85%) with an inv(16) obtained a complete remission, whereas 24 of 35 intensively treated patients (69%) with a t(15;17) obtained a complete remission. The median overall survival of intensively treated patients was 29 months in both cytogenetic subgroups. In the inv(16) subgroup, patients younger than 55 years of age had a longer survival when compared with older patients (P = 0.006). The study supports the observation that t-MDS/t-AML with inv(16) and t(15;17) is often associated with prior therapy with topoisomerase II inhibitors; however, a notable finding was the high frequency of treatment with only radiotherapy, 29% of t(15;17) and 21% of inv(16). Response rates to intensive chemotherapy in this study were comparable to those of de novo disease.
...
PMID:Balanced chromosome abnormalities inv(16) and t(15;17) in therapy-related myelodysplastic syndromes and acute leukemia: report from an international workshop. 1192 Dec 73


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---