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)

Somatically acquired point mutations of AML1/RUNX1 gene have been recently identified in rare cases of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Moreover, germ line mutations of AML1 were found in an autosomal dominant disease, familial platelet disorder with predisposition to AML (FPD/AML), suggesting that AML1 mutants, as well as AML1 chimeras, contribute to the transformation of hematopoietic progenitors. In this report, we showed that AML1 point mutations were found in 6 (46%) of 13 MDS patients among atomic bomb (A-bomb) survivors in Hiroshima. Unlike acute or chronic leukemia patients among A-bomb survivors, MDS patients exposed relatively low-dose radiation and developed the disease after a long latency period. AML1 mutations also were found in 5 (38%) of 13 therapy-related AML/MDS patients who were treated with alkylating agents with or without local radiation therapy. In contrast, frequency of AML1 mutation in sporadic MDS patients was 2.7% (2 of 74). Among AML1 mutations identified in this study, truncated-type mutants lost DNA binding potential and trans-activation activity. All missense mutations with one exception (Gly42Arg) lacked DNA binding ability and down-regulated the trans-activation potential of wild-type AML1 in a dominant-negative fashion. The Gly42Arg mutation that was shared by 2 patients bound DNA even more avidly than wild-type AML1 and enhanced the trans-activation potential of normal AML1. These results suggest that AML1 point mutations are related to low-dose radiation or alkylating agents and play a role distinct from that of leukemogenic chimeras as a result of chromosomal translocations caused by sublethal radiation or topoisomerase II inhibitors.
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PMID:Implications of somatic mutations in the AML1 gene in radiation-associated and therapy-related myelodysplastic syndrome/acute myeloid leukemia. 1239 79

To ascertain the frequency of treatment-related acute myeloid leukemias and myelodysplastic syndromes (t-AML/t-MDS) in an unselected series, we have identified all adult cases analyzed in our department from 1976 to 1993. Further aims were to compare karyotypic features of t-AML/t-MDS with de novo AML/MDS, in our material as well as in 5098 unselected, cyto- genetically abnormal, published cases, and to analyze associations between type of prior therapy and karyotype. Among our 372 AML and 389 MDS, 47 (13%) were t-AML and 62 (16%) were t-MDS. Clonal abnormalities were significantly more common in t-AML and t-MDS than in de novo disease (68% vs 50%, P < 0.05 and 84% vs 45%, P < 0.001, respectively). Among the available 4230 AML and 1629 MDS (the present series and published cases), 14% were t-AML and 15% were t-MDS. In t-AML/t-MDS, the number of anomalies and the ploidy levels differed significantly from de novo cases, with complex and hypodiploid karyotypes being more common in t-AML/t-MDS. In t-AML, unbalanced changes in general, t(1;3), der(1;7), 3p-, -5, 5q-, -7, 7q-, t(9;11), t(11;19), t(11q23), der(12p), -17, der(17p), -18, and -21 were significantly more frequent than in de novo AML. In t-MDS, -5, -7, 7q-, 13q-, der(17p), and -18 were significantly more common. Type of prior treatment correlated significantly with number of anomalies in t-AML and with ploidy levels in t-AML/t-MDS. The frequencies of several aberrations varied with type of therapy, eg, 5q- was more frequent in radiotherapy-associated t-MDS, monosomy 7 was more common in t-AML and t-MDS after treatment with alkylators, and t(11q23) in t-AML was associated with topoisomerase II inhibitors. Abnormalities significantly more common in de novo disease were +8 as a sole anomaly, balanced changes in general, t(8;21), t(9;22), t(15;17), inv(16), and t(21q22) in AML, and -Y, 5q-, and 20q- as sole anomalies and +8 in MDS. The results emphasize the strong association between previous genotoxic exposure and karyotypic features.
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PMID:Pooled analysis of clinical and cytogenetic features in treatment-related and de novo adult acute myeloid leukemia and myelodysplastic syndromes based on a consecutive series of 761 patients analyzed 1976-1993 and on 5098 unselected cases reported in the literature 1974-2001. 1245 41

Regimens of adjuvant chemotherapy for early-stage breast cancer commonly include alkylating agents and anthracyclines. These agents have been associated with treatment-related acute myelocytic leukemia (AML) or myelodysplastic syndrome (MDS). This article reviews the medical literature concerning the incidence, causes, and natural history of treatment-related AML/MDS, with emphasis on the association of these factors with alkylating agents, topoisomerase inhibitors, growth factors, and radiation treatment. Data from 6 completed adjuvant National Surgical Adjuvant Breast and Bowel Project trials that tested regimens containing doxorubicin and cyclophosphamide were reviewed to characterize the incidence of treatment-related AML/MDS. The regimens differed in cyclophosphamide intensity, cumulative cyclophosphamide dose, and the presence or absence of mandated prophylactic support with growth factor and ciprofloxacin. Rates were compared across regimens, by patient age, and by treatment with or without adjuvant in-breast radiation therapy (RT). The relative risk (RR) for the development of treatment-related AML/MDS was greater for patients undergoing the more-intense regimens than for those undergoing standard AC (doxorubicin/cyclophosphamide) regimens (RR, 6.16; P<0.0001). Risk correlated more closely with dose intensity than with cumulative dose, and the data suggested that granulocyte colony-stimulating factor (G-CSF) dose may also be independently correlated with increased risk. Patients who received in-breast RT experienced more secondary AML/MDS than those who did not (RR, 2.38; P=0.006). Patients treated with AC with intensified doses of cyclophosphamide requiring G-CSF support had increased rates of treatment-related AML/MDS, even though the incidence was slight relative to breast cancer relapse. In-breast RT appeared to be associated with an increased risk of AML/MDS.
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PMID:Risk for the development of treatment-related acute myelocytic leukemia and myelodysplastic syndrome among patients with breast cancer: review of the literature and the National Surgical Adjuvant Breast and Bowel Project experience. 1465 72

Therapy-related leukemia and therapy-related myelodysplasia (t-AML/MDS) are serious and increasingly frequent complications of cytotoxic chemotherapy and/or radiotherapy. Two syndromes can be distinguished, one of which has a long latency (5-7 years or more) and is seen following alkylating agents, frequently with an antecedent dysplastic phase. The other has a short latency period (1-3 years), no antecedent dysplastic phase, and is characteristically seen following topoisomerase II inhibitors. Chromosomal abnormalities can confirm t-leuk/MDS and are predictive of poor prognosis, particularly those involving gains and losses of chromosome 7. There is no standard therapy for t-AML/MDS. This review concentrates on the various treatment approaches for t-AML/MDS. Treatment can be aggressive, with curative intent, particularly for patients who are young with no end-organ damage from the prior malignancy or chemotherapy. Various chemotherapy regimens have been designed to overcome the chemoresistance which is generally characteristic of these syndromes. Bone marrow transplantation offers the best chance for cure, and both myeloablative and nonmyeloablative protocols have been designed. Low dose chemotherapy is an option for patients not able to withstand traditional curative regimens and supportive care is a legitimate option for elderly or infirm patients. Multicenter studies are urgently needed to provide data on which clearcut treatment guidelines can be based, taking into account the patient's age, disease status and risk factors.
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PMID:Therapy-related leukemia and myelodysplasia: evolving concepts of pathogenesis and treatment. 1520 99