Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism of benzene toxicity has been extremely difficult to fully characterize. Much progress has been made in assessing the relative potency of benzene metabolites but specific pathways to leukemia remain to be determined. Metabolite and mechanistic studies will have to focus on aplastic anemia and MDS and separate endpoints. This may serve to clarify the array of metabolite effects and consequent disparate effects. Biomarker research can contribute to the understanding of the toxicity process. The significance of understanding benzene toxicity will also lead to better clinical treatment of aplastic anemia and therapy-related MDS and AML, detection of populations particularly susceptible to benzene toxicity, screening of populations with suspected or unknown exposures, and determination of meaningful values for occupational and individual health risk while effectively monitoring ongoing exposures for early signs of toxicity.
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PMID:Scientific update on benzene. 947 33

Myelodysplastic syndromes (MDS) are a heterogeneous and common group of clonal hematological disorders characterized by cytopenias, dysplastic changes of hematopoietic cells, and a high rate of transformation into acute myeloblastic leukemia (AML). MDS provide a clinical model for studying the emergency and progression of malignancy. The initiating events leading to MDS remain almost unknown. Imbalance of proliferative and differentiating capabilities of progenitor hematopoietic cells along with abnormalities in the normal process of apoptosis are involved in both the pathogenesis of MDS and transformation into AML. Multiple genomic lesions, comprising oncogene activation and tumor-suppressor gene inactivation, are probably required. Alkylating agents, cytotoxic drugs targeting topoisomerase II and benzene are the only clear etiological factors identified. Advanced age and great prognostic variability, not explained by the FAB subtype, complicates the design and analysis of clinical trials and therapy-planning. The use of recently developed prognostic scores for selecting the best treatment according to the expected risk is encouraged. In most patients therapy is unsatisfactory. At present, bone marrow transplantation is considered as the only curative approach. A better knowledge of the pathobiology of MDS should be valuable to develop new, more rationale and effective therapies.
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PMID:Etiopathogeny, prognosis and therapy of myelodysplastic syndromes. 949 87

Chromosome aberrations in peripheral blood lymphocytes have been used for many years to monitor human populations exposed to potential carcinogens. Recent reports have confirmed the validity of this approach by demonstrating that elevated levels of chromosome aberrations in lymphocytes are associated with subsequent increased cancer risk, especially for increased mortality from hematological malignancies including acute myeloid leukemia (AML). We postulated that this approach could be improved in two ways: (a) by detecting oncogenic disease-specific aberrations; and (b) by using chromosome painting so that many more metaphases could be analyzed. Numerical and structural aberrations in chromosomes 8 and 21 are commonly observed in AML. In the present study, we painted chromosomes 8 and 21 in lymphocyte metaphases from 43 healthy workers exposed to benzene, an established cause of AML, and from 44 matched controls. To examine dose-response relationships the workers were divided into two groups at the median exposure level, a lower-exposed group (< or = 31 ppm; n = 21), and a higher-exposed group (> 31 ppm; n = 22). Benzene exposure was associated with significant increases in hyperdiploidy of chromosomes 8 (1.2, 1.5, and 2.4 per 100 metaphases; P < 0.0001) and 21 (0.9, 1.1, and 1.9 per 100 metaphases; P < 0.0001). Translocations between chromosomes 8 and 21 were increased up to 15-fold in highly exposed workers (0.01, 0.04, and 0.16 per 100 metaphases; P < 0.0001). In one highly exposed individual, these translocations were reciprocal and were detectable by reverse transcriptase-PCR. These data indicate a potential role for t(8;21) in benzene-induced leukemogenesis and are consistent with the hypothesis that detection of specific chromosome aberrations may be a powerful approach to identify populations at increased risk of leukemia.
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PMID:Increased translocations and aneusomy in chromosomes 8 and 21 among workers exposed to benzene. 960 63

Increased levels of DNA-protein cross-links (DNAPC) have been observed in vitro and in vivo following treatment with a number of chemotherapeutic alkylating agents and topoisomerase II inhibitors, that is, agents that have also been associated with the development of bone marrow depression and acute myelogenous leukemia. The current studies were undertaken to examine the effect of benzene, a bone marrow toxin and human leukemogen, on DNAPC levels in mouse bone marrow cells. Using a K+/sodium dodecyl sulfate (SDS) precipitation assay for DNAPC determination, the results indicate increased DNA-protein cross-link levels in mouse bone marrow cells at 2 and 4 but not 8 h after a single ip injection of 440 mg/kg benzene. Following the administration of multiple hematotoxic benzene doses (440 or 880 mg/kg, 2x/d for 2 d), increases in DNA-protein cross-link levels were either slight or not present. These results suggest that DNAPC induced by benzene are neither cumulative nor persistent lesions. The toxicity of benzene is mediated by a number of number of ring-hydroxylated and ring-opened compounds; therefore the present studies also examined DNAPC levels in mice administered trans,trans-muconaldehyde (MUC), a ring-opened hematotoxic and genotoxic metabolite of benzene. No marked increases in DNAPC levels were observed in CD- mouse bone marrow cells 1-12 h following a single ip injection of 3 mg/kg muconaldehyde. It is possible that multiple doses of MUC are required to induce elevated DNAPC levels in bone marrow cells of mice, since multiple doses are required for MUC-induced hematotoxicity. Other reactive metabolites and/or an interaction of reactive intermediates may also be involved in DNAPC induced by benzene.
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PMID:DNA-protein cross-link levels in bone marrow cells of mice treated with benzene or trans,trans-muconaldehyde. 1009 61

NAD(P)H:quinone oxidoreductase (NQO1) converts benzene-derived quinones to less toxic hydroquinones and has been implicated in benzene-associated hematotoxicity. A point mutation in codon 187 (Pro to Ser) results in complete loss of enzyme activity in homozygous subjects, whereas those with 2 wild-type alleles have normal activity. The frequency of homozygosity for the mutant allele among Caucasians and African Americans is 4% to 5% but is higher in Hispanics and Asians. Using an unambiguous polymerase chain reaction (PCR) method, we assayed nonmalignant lymphoblastoid cell lines derived from 104 patients with myeloid leukemias; 56 had therapy-related acute myeloid leukemia (t-AML), 30 had a primary myelodysplastic syndrome (MDS), 9 had AML de novo, and 9 had chronic myelogenous leukemia (CML). All patients had their leukemia cells karyotyped. Eleven percent of the t-AML patients were homozygous and 41% were heterozygous for the NQO1 polymorphism; these proportions were significantly higher than those expected in a population of the same ethnic mix (P =.036). Of the 45 leukemia patients who had clonal abnormalities of chromosomes 5 and/or 7, 7 (16%) were homozygous for the inactivating polymorphism, 17 (38%) were heterozygous, and 21 (47%) had 2 wild-type alleles for NQO1. Thus, NQO1 mutations were significantly increased compared with the expected proportions: 5%, 34%, and 61%, respectively (P =.002). An abnormal chromosome no. 5 or 7 was observed in 7 of 8 (88%) homozygotes, 17 of 45 (38%) heterozygotes, and 21 of 51 (41%) patients with 2 wild-type alleles. Among 33 patients with balanced translocations [14 involving bands 11q23 or 21q22, 10 with inv(16) or t(15;17), and 9 with t(9;22)], there were no homozygotes, 15 (45%) heterozygotes, and 18 (55%) with 2 wild-type alleles. Whereas fewer than 3 homozygotes were expected among the 56 t-AML patients, 6 were observed; 19 heterozygotes were expected, but 23 were observed. The gene frequency for the inactivating polymorphism (0. 31) was increased approximately 1.4-fold among the 56 t-AML patients. This increase was observed within each of the following overlapping cohorts of t-AML patients: the 43 who had received an alkylating agent, the 27 who had received a topoisomerase II inhibitor, and the 37 who had received any radiotherapy. Thus, the frequency of an inactivating polymorphism in NQO1 appears to be increased in this cohort of myeloid leukemias, especially among those with t-AML or an abnormality of chromosomes 5 and/or 7. Homozygotes and heterozygotes (who are at risk for treatment-induced mutation or loss of the remaining wild-type allele in their hematopoietic stem cells) may be particularly vulnerable to leukemogenic changes induced by carcinogens.
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PMID:Prevalence of the inactivating 609C-->T polymorphism in the NAD(P)H:quinone oxidoreductase (NQO1) gene in patients with primary and therapy-related myeloid leukemia. 1039 48

This study, using the CBA/Ca mouse as a model, compares genetic lesions associated with radiation- and benzene-induced acute leukemias. Specific types of leukemia included in the analyses are radiation-induced acute myeloid leukemia (ML), and benzene-induced lymphoblastic leukemias, lymphomas, or mix-lineage leukemias. These leukemias have histopathological characteristics similar to those seen in human acute leukemias. G-band cytogenetic analysis showed that specific deletions involving regions D-E of one copy of mouse chromosome 2 [del(2)(D-E)] were frequently associated in both radiation- and benzene-induced acute leukemias. In addition, translocations of chr2(D-E) were also observed in some cases. These results suggest an important role of chr2 (D-E) deletions and translocations in the development of radiation- and benzene-induced murine acute leukemias. Fluorescence in situ hybridization with DNA probes specific for 2(D-E), constructed in our laboratory by means of chromosomal microdissection and PCR amplification, also demonstrate 2(D-E) deletions and/or translocations in these leukemic cells. Aneuploidy of chromosomes 3, 15, 16, and Y were also frequently detected in benzene-induced leukemic cells with or without lesions on chr2. These cytogenetic findings support the previous observations that metabolites of benzene lead to spindle-fiber disruption or abnormal cytokinesis in exposed animals. In summary, genetic instabilities observed in leukemic cells isolated from mice that had developed leukemia after exposure to radiation or benzene are syntenic with those frequently detected in patients with myelodysplastic syndrome, acute ML, and acute lymphoblastic leukemia. Thus, the CBA/Ca mouse has several characteristics that make it an excellent model for the study of radiation or benzene leukemogenesis in humans.
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PMID:Characterization of genetic instability in radiation- and benzene-induced murine acute leukemia. 1051 76

Risk estimates and cause and effect determinations are directly dependent on exposure and dose-response relationships. Recently, relative risks and excess cancer mortality attributed to occupational benzene exposure have been published in collaborative studies conducted by Chinese investigators and scientists from the National Cancer Institute. The results of these studies suggest increased risk of acute nonlymphocytic leukemia at relatively low benzene concentrations and associations with cancers not previously associated with benzene exposure. These studies are potentially important due to their size and potential to more thoroughly investigate the link between benzene exposure and cancer. However, there are questions concerning the validity of exposure and dose estimates supporting relative risk characterizations in these studies. Apparent discrepancies between modeled exposure and dose estimates and sources of actual measured exposure information and clinical markers of benzene toxicity raise serious concerns questioning the reliability of relative risk and cancer associations stated in these studies.
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PMID:An evaluation of modeled benzene exposure and dose estimates published in the Chinese-National Cancer Institute collaborative epidemiology studies. 1062 Apr 74

Incidence rates for non-Hodgkin's lymphoma (NHL) have been rising throughout the world for several decades, and no convincing explanation exists for the majority of this increase. The commonest subtypes of NHL have no well-defined aetiological factors but lymphoma development has been linked with exposure to a variety of chemicals, including nitrates, pesticides, herbicides, and solvents. Benzene, a solvent and important constituent of petrochemical products, is a potent lymphomagen in experimental animals and high-dose exposure in humans is associated with both acute myeloid leukaemia and NHL. Much current interest centres on the possibility that environmental benzene exposure in the general public may underlie a proportion of the increase in NHL. Seventy per cent of benzene exposure in the environment is derived from vehicle exhaust emissions, whose increase has closely paralleled the rise in frequency of the disease. Mathematical modelling has been used to calculate an acceptable concentration of benzene in air based on risk estimates derived from industrial exposure, but the recommended target concentration in the U.K. of 1 ppb is regularly exceeded in urban locations. Detailed investigation of the health effects of low-level benzene exposure awaits an accurate assay for quantifying long-term human exposure. The (32)P post-labelling technique for the detection of toxin-specific DNA adducts is extremely sensitive and has been applied in the biomonitoring of exposure to a number of carcinogens, but benzene-DNA adducts have to date proved elusive of detection.
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PMID:Benzene and non-Hodgkin's lymphoma. 1062 42

Chronic exposure to high concentrations of benzene is associated with an increased incidence of myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). Studies of patients occupationally exposed to benzene show a pattern of cytogenetic aberrations involving loss of all or part of chromosomes 5 and/or 7 as well as trisomy 8 and we have previously reported that hydroquinone (HQ) induces deletions of 5, 7 and 8. Benzene metabolism is a requirement for bone marrow toxicity and the phenolic metabolites, HQ and catechol (CAT), have been implicated in benzene hematotoxicity. A research project was designed to determine whether CAT by itself and in conjunction with HQ could directly induce loss of chromosome 5 and/or 7 and gain of chromosome 8. Using fluorescence in situ hybridization with chromosome-specific 5, 7, and 8 probes we demonstrate that 5 to 150 uM CAT does not produce chromosomal aberrations, however CAT and 25 uM HQ can act in synergy to induce dose dependent loss of these chromosomes. In addition HQ/CAT selectively induces -5q which is not observed for HQ only. These results demonstrate for the first time that CAT/HQ act in synergy to induce specific chromosome loss found in secondary MDS/AML.
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PMID:The benzene metabolites hydroquinone and catechol act in synergy to induce dose-dependent hypoploidy and -5q31 in a human cell line. 1070 50

Cigarette smoking is associated with an increased risk of leukemia; benzene, an established leukemogen, is present in cigarette smoke. By combining epidemiologic data on the health effects of smoking with risk assessment techniques for low-dose extrapolation, we assessed the proportion of smoking-induced total leukemia and acute myeloid leukemia (AML) attributable to the benzene in cigarette smoke. We fit both linear and quadratic models to data from two benzene-exposed occupational cohorts to estimate the leukemogenic potency of benzene. Using multiple-decrement life tables, we calculated lifetime risks of total leukemia and AML deaths for never, light, and heavy smokers. We repeated these calculations, removing the effect of benzene in cigarettes based on the estimated potencies. From these life tables we determined smoking-attributable risks and benzene-attributable risks. The ratio of the latter to the former constitutes the proportion of smoking-induced cases attributable to benzene. Based on linear potency models, the benzene in cigarette smoke contributed from 8 to 48% of smoking-induced total leukemia deaths [95% upper confidence limit (UCL), 20-66%], and from 12 to 58% of smoking-induced AML deaths (95% UCL, 19-121%). The inclusion of a quadratic term yielded results that were comparable; however, potency models with only quadratic terms resulted in much lower attributable fractions--all < 1%. Thus, benzene is estimated to be responsible for approximately one-tenth to one-half of smoking-induced total leukemia mortality and up to three-fifths of smoking-related AML mortality. In contrast to theoretical arguments that linear models substantially overestimate low-dose risk, linear extrapolations from empirical data over a dose range of 10- to 100-fold resulted in plausible predictions.
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PMID:The contribution of benzene to smoking-induced leukemia. 1075 92


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