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

GSTM1 and GSTT1 are polymorphic genes. Absence of enzyme activity is due to homozygous inherited deletion of the gene, reducing detoxification of carcinogens such as epoxides and alkylating agents and potentially increasing cancer risk. We hypothesized that GST null genotype would increase risk of acute myeloid leukemia and myelodysplasia (AML/MDS) in children. DNA was extracted from bone marrow slides of 292 AML/MDS patients. PCR amplification was used to assign GSTM1 and GSTT1 genotypes for cases and controls. Given that the frequency of the null genotype varies by ethnicity and that the majority of the cases were Caucasian, analyses were restricted to 232 white (non-Hispanic) cases and 153 Caucasian non cancer controls. The frequency of GSTM1 null was significantly increased in AML/MDS cases compared with controls [64 versus 47%; odds ratio (OR), 2.0 [95% confidence interval (CI), 1.3-3.1]; P = 0.001], whereas the frequency of GSTT1 null genotype in AML/MDS cases was not statistically different from controls. AML comprises biologically distinct subtypes, and a test for homogeneity revealed a statistically significant difference among subtypes (P = 0.04; df, 8) for GSTM1 only. In particular, there was an increased frequency of GSTM1 null genotypes in French-American-British groups M3 [82%; n = 22; OR, 5.1 (95% CI, 1.6-21.3)] and M4 [72%; n = 53; OR, 2.9 (95% CI, 1.4-6.0)]. We conclude that the GSTM1 null genotype is a significant risk factor for childhood AML, particularly French-American-British groups M3 and M4. This may indicate an important role for exogenous carcinogens in the etiology of childhood AML.
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PMID:Glutathione S-transferase polymorphisms in children with myeloid leukemia: a Children's Cancer Group study. 1086 89

A major obstacle to successful cancer chemotherapy is the development of multidrug resistance (MDR). The previous study revealed that a doxorubicin-resistant AML subline (AML-2/DX100) overexpressed an MDR-associated protein (MRP) but not P-glycoprotein. The AML-2/DX100 also showed various levels of resistance to daunorubicin and vincristine but was paradoxically sensitive to hydrogen peroxide (5-fold), t-butyl hydroperoxide (3-fold), and paraquat (2-fold) when compared to the drug-sensitive parental AML-2 cells (AML-2/WT). We compared the activities of antioxidant enzymes to detoxify reactive oxygen species (ROS), including superoxide dismutases, glutathione S-transferase, catalase, glutathione reductase, glutathione peroxidase, and glucose-6-phosphate dehydrogenase in both AML-2/WT and AML-2/DX100. Interestingly, of these antioxidant enzymes, catalase activity of AML-2/DX100 decreased significantly to about one-third that of AML-2/WT (P < 0.000005). The decreased activity of catalase was due to reduced expression of the catalase gene; confirmed by Western blot and reverse transcription-polymerase chain reaction (RT-PCR) analyses. The decreased activity of catalase was maintained even in the absence of doxorubicin for 3 months as well as by the treatment of probenecid, an MRP inhibitor. In addition, there was no difference in catalase activity between HL-60 and another MRP-overexpressing subline HL-60/Adr. Taken together, the paradoxical increase in the sensitivity of an MRP-overexpressing AML-2/DX100 in response to peroxides and paraquat is due to the down-regulation of catalase gene expression, which totally independent of overexpression of MRP. It is therefore possible that decreased catalase activity could be exploited as an Achilles' heel in resistant cells such as this.
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PMID:Down-regulation of catalase gene expression in the doxorubicin-resistant AML subline AML-2/DX100. 1117 67

Cyclin A1 is tissue-specifically expressed during spermatogenesis, but it is also highly expressed in acute myeloid leukemia (AML). Its pathogenetic role in AML and in the cell cycle of leukemic blasts is unknown. B-myb is essential for G1/S transition and has been shown to be phosphorylated by the cyclin A2/cdk2 complex. Here it is demonstrated that cyclin A1 interacts with the C-terminal portion of B-myb as shown by glutathione S-transferase (GST) precipitation. This interaction is confined to cyclin A1 because binding could not be detected between cyclin A2 and B-myb. Also, cdk2 was not pulled down by GST-B-myb from U937 lysates. In addition, co-immunoprecipitation of cyclin A1 and B-myb in leukemic cells evidenced protein interaction in vivo. Baculovirus-expressed cyclin A1/cdk2 complexes were able to phosphorylate human as well as murine B-myb in vitro. Tryptic phosphopeptide mapping revealed that cyclin A1/cdk2 complexes phosphorylated the C-terminal part of B-myb at several sites including threonine 447, 490, and 497 and serine 581. These phosphorylation sites have been demonstrated to be important for the enhancement of B-myb transcriptional activity. Further studies showed that cyclin A1 cooperated with B-myb to transactivate myb binding site containing promoters including the promoter of the human cyclin A1 gene. Taken together, the data suggest that cyclin A1 is a tissue-specific regulator of B-myb function and activates B-myb in leukemic blasts. (Blood. 2001;97:2091-2097)
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PMID:Cyclin A1 directly interacts with B-myb and cyclin A1/cdk2 phosphorylate B-myb at functionally important serine and threonine residues: tissue-specific regulation of B-myb function. 1126 76

Genetic approaches to understanding the etiology of the acute leukemias are beginning to deliver meaningful insights. Polymorphic variants in xenobiotic metabolizer loci were a natural starting point to study the relevance of these changes. The finding that glutathione S-transferase (GST) T1 null variants increase leukemia risk has implicated oxidative stress in hematopoietic stem cells as an important etiological factor in acute myeloid leukemia (AML). The importance of these enzyme systems in handling specific substrates has also been confirmed by the finding of an increased risk of therapy-related leukemia in individuals with underactive variants of GSTP1 who have been exposed to a chemotherapeutic agent metabolized by this enzyme. Benzene is a well-recognized leukemogen, and genetic variants in its metabolic pathway can modulate the risk of leukemia following exposure. In particular, underactive variants of the NAD(P)H:quinone oxidoreductase 1 gene (NQO1) seem to increase the risk of AML. Other enzymes within the pathway are proving more difficult to study because of the absence of variants that significantly affect the biological activity of the enzyme under study. No effect of the myeloperoxidase (MPO) gene variants in altering the risk of AML has been seen in our studies. Another pathway recently shown to be important in determining leukemia risk is folic acid metabolism, particularly important in predisposition to acute lymphocytic leukemia (ALL). Polymorphic variants of the methylenetetrahydrofolate reductase gene (MTHFR) which impair its activity have been shown to be associated with a protective effect. This is thought to be due to an increased availability of nucleotide precursors for incorporation into DNA. This finding implicates misincorporation of uracil into DNA as an important mechanism of leukemic change in lymphoid precursors. Future studies will extend these observations but will require biological material collected from large well-controlled epidemiological studies. The technological challenges imposed by the high throughput of samples required by these studies are currently being addressed.
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PMID:Metabolic enzyme polymorphisms and susceptibility to acute leukemia in adults. 1208 44

The etiology of acute myeloid leukemia (AML) is largely unknown. Biologic and epidemiologic data implicate exogenous toxicants, including cytotoxic drugs, benzene, radiation, and cigarette smoking. Allelic variation in genes encoding enzymes such as NADP(H) quinone oxidoreductase (NQO1) and glutathione S-transferase T1 (GSTT1) that metabolize environmental toxicants predispose to subtypes of AML, including therapy-related AML. We assayed NRAS oncogene mutation and FLT3 internal tandem duplication in 447 AML patients with an abnormal karyotype treated in Medical Research Council (MRC) AML clinical trials. Functional allelic variant frequencies in genes encoding carcinogen-metabolizing enzymes GSTT1, GSTM1, CYP1A1, CYP2D6, CYP2C19, SULT1A1, and NQO1 were previously determined for this cohort. FLT3 internal tandem duplication (ITD) frequency was 17%, and NRAS mutation 12% for the entire cohort. The 2 mutations were found together in only 4 patients. No association was found between enzyme allelic variant frequencies and the presence of FLT3 ITD for the entire cohort or within cytogenetic subgroups. CYP1A1*2B (Val) high-inducibility variant allele was overrepresented in patients with NRAS mutation compared with no mutation, for (1) the entire AML cohort (n = 8/53 vs 26/371; odds ratio [OR] = 2.36; 95% confidence interval [CI] 1.01-5.53) and (2) the poor-risk karyotype group (n = 6/14 vs 4/89; OR = 15.94; 95% CI 3.71-68.52) comprising patients with partial/complete deletion of chromosome 5 or 7, or abnormalities of chromosome 3. The CYP1A1*2B allele may predispose to the development of these subgroups of AML by augmented phase 1 metabolism to highly reactive intermediates of CYP1A1 substrates, including polycyclic aromatic hydrocarbons, or by generation of oxidative stress as a metabolic by-product.
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PMID:CYP1A1*2B (Val) allele is overrepresented in a subgroup of acute myeloid leukemia patients with poor-risk karyotype associated with NRAS mutation, but not associated with FLT3 internal tandem duplication. 1246 38

The purpose of this study was to investigate the adaptive mechanisms of hydrogen peroxide-supersensitive AML cells against the reactive oxygen species (ROS). Their scavenging capacity against ROS was determined using a fluorometric probe in the doxorubicin-resistant AML-2/DX100 cell characterized by the down-regulation of catalase. AML-2/DX100 cells had more scavenging capacity against endogenous pro-oxidants than did the parental cells AML-2/WT, suggesting that an anti-oxidant adaptation against ROS occurred. cDNA microarrays for 8000 human genes revealed that among 21 anti-oxidant genes, each four gene was up- and down-regulated more than 1.5-fold in AML-2/DX100 compared with AML-2/WT. The mRNA expression of glutathione S-transferase Pi, peroxiredoxin 2, thioredoxin 2, and glutaredoxin was elevated whereas that of peroxiredoxin 3, metallothionein-1F, superoxide dismutase 2, and thioredoxin reductase 1 was depressed. The result indicates that the down-regulation of certain anti-oxidant mechanisms can be compensated for by the up- and down-regulation of the other anti-oxidant mechanisms.
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PMID:Anti-oxidant adaptation in the AML cells supersensitive to hydrogen peroxide. 1515 39

The t(8;21) translocation is one of the most frequent chromosome abnormalities in acute myeloid leukemia. This translocation creates a fusion between the acute myelogenous leukemia 1 (AML1, a transcription factor) gene on chromosome 21 and the eight-twenty-one (ETO, a zinc finger nuclear protein) gene on chromosome 8, leading to the repression of certain AML1 target genes. We cloned NHR3 domain coding fragment into vector pGEX-6p-1 using PCR and obtained recombinant plasmid pGEX-6p-1-NHR3, which can be induced to stably overexpress fusion protein in E. coli. Through the purification on GST affinity chromatography column and PreScission protease cleavage, a large amount of NHR3 protein with high purity was obtained. In order to avoid possible interference of some strong negative charged molecules, NHR3 protein was further purified by Mono Q anion exchange chromatography. The NHR3 crystals were grown with hanging drop/vapor diffusion method and the first crystals appeared after four weeks at 18 degrees in 0.2 M Tris-sodium citrate dihydrate, 0.1 M sodium cacodylate, pH 6.5, and 30% iso-propanol (V/V). ESI mass spectrum showed that the molecular weight of this domain was in agreement with its primary structure sequence prediction, and circular dichroism spectral data (190-250 nm) showed that NHR3 had a well-defined secondary structure of 25.9% alpha-helix, 23.2% random coil and 50.9% turn, which was consistent with GOV4 software prediction.
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PMID:Cloning, expression, purification and crystallization of NHR3 domain from acute myelogenous leukemia-related protein AML1-ETO. 1529 50

The study was aimed to investigate the expression level of TRF1 protein in human acute leukemia and relationship between expression level of TRF1 protein and activity of telomerase. A quantitative Western blot technique was developed using anti-TRF1(33 - 277) monoclonal antibody and GST-TRF1 fusion protein as a standard to further determine the expression level of TRF1 protein in total proteins extracted from clinical specimens. 20 cases of acute leukemias were studied when 11 normal volunteer's bone marrow was used as control. The results showed that the expression level of TRF1 protein in normal bone marrow (2.217 +/- 0.461 microg/microl) was significantly higher than that in bone marrow of acute leukemia patients (0.754 +/- 0.343 microg/microl) (P < 0.01). There was no remarkable difference of expression level of TRF1 protein between ALL and ANLL (0.628 +/- 0.281 microg/microl vs 0.844 +/- 0.360 microg/microl, P > 0.05). After chemotherapy, TRF1 expression level of patients with complete remission raised (0.772 +/- 0.307 microg/microl vs 1.683 +/- 0.344 microg/microl, P < 0.01), but lower than that of normal (2.217 +/- 0.461 microg/microl, P < 0.01). TRF1 expression level of patients without complete remission was not remarkable different after chemotherapy (0.726 +/- 0.443 microg/microl vs 0.894 +/- 0.338 microg/microl, P > 0.05). TRF1 expression level of patients with complete remission was higher than that in patients without complete remession (1.683 +/- 0.344 microg/microl vs 0.894 +/- 0.338 microg/microl, P < 0.01). For all sample the telomerase activity was determined. It was confirmed that the activity of telomerase in normal bone marrow was lower than that in bone marrow of acute leukemia patients (0.125 +/- 0.078 microg/microl vs 0.765 +/- 0.284 microg/microl, P < 0.01). There was no significantly difference of expression level of TRF1 protein between ALL and ANLL (0.897 +/- 0.290 microg/microl vs 0.677 +/- 0.268 microg/microl, P > 0.05). After chemotherapy, telomerase activity of patients with complete remission reduced (0.393 +/- 0.125 microg/microl), but higher than that of normal (0.125 +/- 0.078 microg/microl, P < 0.01). It is concluded that expression level of TRF1 protein in AL patients is significantly decrese and associated with therapeutic efficaciousness and the activity of telomerase (P < 0.001).
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PMID:[Expression level of TRF1 protein in human acute leukemia and its relationship with activity of telomerase]. 1709 76

Functional polymorphisms in the genes encoding detoxification enzymes could modify the response to treatment in acute myeloid leukemia and therefore affect the final clinical outcome. In the present study, we genotyped 153 patients diagnosed with de novo acute myeloid leukemia (AML) to clarify the influence of the genetic polymorphisms CYP1A1*2A, CYP3A4*1B, CYP2E1*5B, del{GSTT1}, del{GSTM1}, and NQO1*2 on disease outcome. The del{GSTM1} showed a higher frequency in females (62%) than in males (41%) (P=0.01). The number of functional NQO1 alleles influenced the response to induction therapy; 81% (55/68) NQO1-negative patients, 69% (28/41) heterozygous patients, and 27% (2/7) homozygous patients achieved complete remission (CR) (P=0.04). The presence of GST deletions was associated with a lower probability of disease-free survival (DFS) and this effect was more relevant in male patients. Males with del{GSTM1} showed a 28% DFS versus 57% DFS for undeleted GSTM1 (P=0.04). Similarly, males with undeleted GSTM1 and GSTT1 showed a 64% DFS versus 34% DFS for males with at least one GST deletion (P=0.05). This study suggests that the NQO1*2 polymorphism is relevant to the patient's response to induction therapy and that GST deletions influence treatment outcome after chemotherapy, especially in male patients.
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PMID:The GST deletions and NQO1*2 polymorphism confers interindividual variability of response to treatment in patients with acute myeloid leukemia. 1711 47

The t(10;11)(p13;q14) translocation leads to the fusion of the CALM and AF10 genes. This translocation can be found as the sole cytogenetic abnormality in acute lymphoblastic leukemia, acute myeloid leukemia and in malignant lymphomas. The expression of CALM/AF10 in primary murine bone marrow cells results in the development of an aggressive leukemia in a murine bone marrow transplantation model. Using a yeast two-hybrid screen, we identified the lymphoid regulator Ikaros as an AF10 interacting protein. Interestingly, Ikaros is required for normal development of lymphocytes, and aberrant expression of Ikaros has been found in leukemia. In a murine model, the expression of a dominant negative isoform of Ikaros causes leukemias and lymphomas. The Ikaros interaction domain of AF10 was mapped to the leucine zipper domain of AF10, which is required for malignant transformation both by the CALM/AF10 and the MLL/AF10 fusion proteins. The interaction between AF10 and Ikaros was confirmed by GST pull down and co-immunoprecipitation. Coexpression of CALM/AF10 but not of AF10 alters the subcellular localization of Ikaros in murine fibroblasts. The transcriptional repressor activity of Ikaros is reduced by AF10. These results suggest that CALM/AF10 might interfere with normal Ikaros function, and thereby block lymphoid differentiation in CALM/AF10 positive leukemias.
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PMID:The leukemogenic CALM/AF10 fusion protein alters the subcellular localization of the lymphoid regulator Ikaros. 1803 64


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