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)

Both WT1 and PRAME are highly expressed in acute myeloid leukemia (AML) patients. To assess the efficacy of their simultaneous detection for the purpose of monitoring minimal residual disease (MRD), we used real-time quantitative RT-PCR to quantify both WT1 and PRAME transcript levels in the bone marrow of 204 newly diagnosed AML patients, and 21 patients were serially monitored for a median of 11 months. The 22 normal bone marrow samples which served as controls collectively expressed low levels of WT1 and PRAME. An increase of >1-log over the upper limit of normal bone marrow was defined as positive. The positive rates of WT1 and PRAME for all patients were 79.2% and 55.4%, respectively. For the 108 patients lacking a specific fusion gene, the positive rate of WT1 was significantly higher than that of PRAME (76.9% vs. 35.2%, P<0.001). PRAME was positive in 9/25 WT1 (-) patients and the log increase of PRAME was higher than that of WT1 in 12/83 WT1 (+) patients. Dynamic patterns of WT1 and PRAME during follow-up showed that a consistent elevation or a rise over time to exceed the normal range predicted clinical relapse. The exception was that one patient's WT1 significantly decreased at relapse compared to diagnosis. Therefore, a simultaneous detection of WT1 and PRAME might not only provide AML patients with either a positive or a more sensitive molecular marker for MRD monitoring. Moreover, it might also avoid false negativity in the case of expression alteration.
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PMID:Expression patterns of WT1 and PRAME in acute myeloid leukemia patients and their usefulness for monitoring minimal residual disease. 1926 25

Cyclin A1 is a cell cycle protein that is expressed in testes, brain and CD34-positive hematopoietic progenitor cells. Cyclin A1 is overexpressed in a variety of myeloid leukemic cell lines and in myeloid leukemic blasts. Transgenic cyclin A1 overexpressing mice develop acute myeloid leukemia with low frequency. In this study, we looked for putative target genes of cyclin A1 in hematopoietic cells. Microarray analysis of U937 myeloid cells overexpressing cyclin A1 versus conrol cells detected 35 differential expressed genes, 21 induced and 14 repressed ones upon cyclin A1 overexpression. Among the differentially expressed genes WT1 was chosen for further analysis. Repression of WT1 expression was confirmed on the mRNA and protein level. In addition, WT1 expression was higher in bone marrow, liver and ovary of cyclin A1-/- mice. Isoform analysis showed a profound change of the WT1 isoform ratio in U937 cyclin A1-overexpressing versus control cells. Functional analysis revealed an inhibition of colony growth when WT1 isoforms were transfected into U937 cells, which was not affected by the overexpression of cyclin A1. In addition, overexpression of the WT1-/+ isoform induced a G1 cell cycle arrest which was abrogated upon cotransfection with cyclin A1. This study identified WT1 as a repressed target of cyclin A1 and suggests that the suppression of WT1 in cyclin A1-overexpressing leukemias might play a role in the growth and suppression of apoptosis in these leukemic cells.
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PMID:Cyclin A1 regulates WT1 expression in acute myeloid leukemia cells. 1908 85

To evaluate the incidence and clinical impact of WT1 gene mutations in younger adult patients with cytogenetically normal acute myeloid leukemia (CN-AML), sequencing of the complete coding region was performed in diagnostic samples from 617 patients who were treated on 3 German-Austrian AML Study Group protocols. WT1 mutations were identified in 78 (12.6%) of the 617 patients; mutations clustered in exon 7 (54 of 78) and exon 9 (13 of 78), but also occurred in exons 1, 2, 3, and 8. WT1 mutations were significantly associated with younger age, higher serum lactate dehydrogenase levels, higher blood blast counts, and the additional presence of FLT3-ITD (P < .001) and CEBPA mutations (P = .004). There was no difference in relapse-free survival and overall survival between patients with (WT1(mut)) or without WT1 mutations. Subset analysis showed that patients with the genotype WT1(mut)/FLT3-ITD(pos) had a lower complete remission rate (P = .003) and an inferior relapse-free survival (P = .006) and overall survival (P < .001) compared with those with the genotype WT1(mut)/FLT3-ITD(neg). In conclusion, in our large cohort of younger adults with CN-AML, WT1 mutation as a single molecular marker did not impact on outcome. However, our data suggest a negative impact of the genotype WT1(mut)/FLT3-ITD(pos).
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PMID:Prognostic impact of WT1 mutations in cytogenetically normal acute myeloid leukemia: a study of the German-Austrian AML Study Group. 1922 Oct 39

Acute myeloid leukemia (AML) with t(7;11)(p15;p15), which results in a NUP98-HOXA9 fusion, is a distinct entity, but this subtype has not been characterized in detail. In a comprehensive study comparing 11 such patients with another 482 adult patients, we found that those with t(7;11) were younger (P=0.0076) and female (P=0.0111), with almost all having the M2-subtype of AML (P<0.0001). Even when those with low-risk karyotypes were excluded, patients with t(7;11) had poorer overall survival than the other AML group (median 13.5 and 20 months, respectively, P=0.045) and poorer relapse-free survival (median 6 and 12 months, respectively, P=0.003). The NUP98-HOXA9 fusion was strongly associated with KRAS and WT1 mutations (P=0.015 and P=0.0018, respectively). We characterized four varieties of this fusion, among which NUP98 exon 12/HOXA9 exon 1b was present in all 11 patients. We developed a highly sensitive and specific assay to quantify the abundance of leukemic cells, and found that the fusion remained detectable in morphological complete remission, even after allogeneic stem cell transplantation, suggesting that this disease was highly refractory to very intensive treatment. AML with NUP98-HOXA9 fusion therefore appears to have a distinct clinical and biological profile, and should be regarded as a poor prognostic group.
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PMID:Acute myeloid leukemia bearing t(7;11)(p15;p15) is a distinct cytogenetic entity with poor outcome and a distinct mutation profile: comparative analysis of 493 adult patients. 1922 39

A standardized, sensitive and universal method for minimal residual disease (MRD) detection in acute myeloid leukemia (AML) is still pending. Although hyperexpression of Wilms' tumor (WT1) gene transcript has been frequently proposed as an MRD marker in AML, wide comparability of the various methods used for evaluating WT1 expression has not been given. We established and standardized a multicenter approach for quantifying WT1 expression by quantitative reverse transcriptase PCR (qRT-PCR), on the basis of a primer/probe set combination at exons 6 and 7. In a series of quality-control rounds, we analyzed 69 childhood AML samples and 47 normal bone marrow (BM) samples from 4 participating centers. Differences in the individual WT1 expressions levels ranged within <0.5 log of the mean in 82% of the cases. In AML samples, the median WT1/1E+04 Abelson (ABL) expression was 3.5E+03 compared with that of 2.3E+01 in healthy BM samples. As 11.5% of childhood AML samples in this cohort harbored WT1 mutations in exon 7, the effect of mutations on WT1 expression has been investigated, showing that mutated cases expressed significantly higher WT1 levels than wild-type cases. Hence, our approach showed high reproducibility and applicability, even in patients with WT1 mutations; therefore, it can be widely used for the quantitation of WT1 expression in future clinical trials.
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PMID:Standardization of WT1 mRNA quantitation for minimal residual disease monitoring in childhood AML and implications of WT1 gene mutations: a European multicenter study. 1932 6

Owing to the heterogeneity of AML, the indication for allogeneic SCT (allo-SCT) requires an exact definition of the individual subentity and risk category. A comprehensive diagnostic approach is needed, which combines cytomorphology, cytogenetics, FISH, molecular genetics and immunophenotyping. Whereas the categorization in three prognostic karyotype groups is well established, rare recurrent aberrations as the unfavorable t(8;16)(p11;p13), inv(3)(q21q26) and t(6;9)(p23;q34) must also be considered. In normal karyotype, PCR analyses reveal prognostically relevant mutations in >85% of cases, and a molecular data set composed of the FLT3-ITD, MLL-PTD, NPM1 and CEBPA mutations was found able to guide the selection of patients for allo-SCT. Some novel markers as the WT1 mutations might further contribute to risk stratification in normal karyotype. The panel of minimal residual disease parameters is being expanded at this time, for example, by quantitative PCR for the NPM1 mutations. Immunophenotyping allows the definition of leukemia-associated phenotypes in nearly all cases, but its position in the indication to allo-SCT has to be validated. Thus, the optimization of the indication to allo-SCT is an ongoing process that should remain in continuous interaction with the increasing panel of known genetic markers and diagnostic methods.
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PMID:Interactive diagnostics in the indication to allogeneic SCT in AML. 1936 29

Real-time quantitative reverse transcriptase polymerase chain reaction method was established for detecting the expression levels of WT1 gene and WT1+17AA isoforms in 226 acute myeloid leukemia (AML) bone marrow (BM) cells. The results showed that WT1 gene was 2-3 logarithms expressed more in AML BM cells at initial diagnosis or relapse than in normal BM cells (p<0.001), with predominant WT1+17AA isoforms expression (the ratio of WT1+17AA/WT1 more than 0.50). Interestingly the ratio of WT1+17AA/WT1 was statistically higher in relapsed AMLs than in initially diagnosed (p=0.01), speculating that WT1+17AA isoforms might participate in AML relapse.
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PMID:High expression of WT1 gene in acute myeloid leukemias with more predominant WT1+17AA isoforms at relapse. 1941 92

Minimal residual disease may help to establish clinical decisions in patients with AML. WT1 offers the possibility to analyze those cases without currently known underlying genetic abnormalities. To compare the value of chimeric specific quantitative PCR with WT1 PCR in CBF acute leukemia, 445 samples from 96 AML (49 AML1-ETO+ and 47 CBFB-MYH11+) cases were included in the study. For each sample AML1-ETO or CBFB-MYH11 levels obtained using the conditions of the BIOMED group were compared with the results of WT1 levels using sensitive primers and conditions. Simultaneously, normal range expression of WT1 was established using RNA obtained from eight healthy donors. WT1 mutations were also investigated both at RNA and at the genomic level. The majority of CBF samples showed rises in WT1 levels (88.7%) at diagnosis. However, 18% of AML1-ETO showed WT1 levels below 250 copies in contrast with 5% CBFB-MYH11 cases. WT1 mutation was not detected in any case (70 diagnostic samples). We found correlation between WT1 levels at diagnosis and the CD34 blast population estimated by flow cytometry in CBFB-MYH11+ cases. We found no association between WT1 levels and clinical outcome. There was a high concordance between chimeric transcript analysis and WT1 levels in CR patients. Concordance was also high in relapsed patients (78% in AML1-ETO and 98% in CBFB-MYH11+ cases). Both WT1 and specific chimeric transcript identified and rescued false negative results of the other test. Additional studies are needed to determine whether the rare discrepancies are a reflection of the cooperative nature of WT1 overexpression or a consequence of the uneven distribution in the leukemic population. WT1 is a powerful MRD tool even in cases with currently available molecular targets.
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PMID:WT1 monitoring in core binding factor AML: comparison with specific chimeric products. 1942 34

PURPOSE To determine the prognostic importance of the meningioma 1 (MN1) gene expression levels in the context of other predictive molecular markers, and to derive MN1 associated gene- and microRNA-expression profiles in cytogenetically normal acute myeloid leukemia (CN-AML). PATIENTS AND METHODS MN1 expression was measured in 119 untreated primary CN-AML adults younger than 60 years by real-time reverse-transcriptase polymerase chain reaction. Patients were also tested for FLT3, NPM1, CEBPA, and WT1 mutations, MLL partial tandem duplications, and BAALC and ERG expression. Gene- and microRNA-expression profiles were attained by performing genome-wide microarray assays. Patients were intensively treated on two first-line Cancer and Leukemia Group B clinical trials. Results Higher MN1 expression associated with NPM1 wild-type (P < .001), increased BAALC expression (P = .004), and less extramedullary involvement (P = .01). In multivariable analyses, higher MN1 expression associated with a lower complete remission rate (P = .005) after adjustment for WBC; shorter disease-free survival (P = .01) after adjustment for WT1 mutations, FLT3 internal tandem duplications (FLT3-ITD), and high ERG expression; and shorter survival (P = .04) after adjustment for WT1 and NPM1 mutations, FLT3-ITD, and WBC. Gene- and microRNA-expression profiles suggested that high MN1 expressers share features with high BAALC expressers and patients with wild-type NPM1. Higher MN1 expression also appears to be associated with genes and microRNAs that are active in aberrant macrophage/monocytoid function and differentiation. CONCLUSION MN1 expression independently predicts outcome in CN-AML patients. The MN1 gene- and microRNA-expression signatures suggest biologic features that could be exploited as therapeutic targets.
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PMID:Prognostic importance of MN1 transcript levels, and biologic insights from MN1-associated gene and microRNA expression signatures in cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study. 1945 32

WT1 gene expression has been proposed as a useful marker of minimal residual disease in leukaemia. Its utility in paediatric haematopoietic stem cell transplantation (HSCT) has not been studied. We studied the prognostic value of WT1 expression in peripheral blood prior to HSCT in 36 children with acute myeloid leukaemia (AML). Samples were obtained 2 weeks pre-transplant to determine the level of WT1 expression. WT1 expression was normalized using K562 cells as a control and a relative value of 0.5 was chosen as the cut-off point between high and low WT1 expression. The median level of pre-transplant WT1 expression in the 36 patients was 0.09 (range 0.0001-11.0), with 11 patients having WT1 >or= 0.5 and 25, WT1 < 0.5. After HSCT, 76% of patients with high pre-transplant WT1 expression relapsed, in contrast to 0% of the patients with low WT1 expression. Those with high WT1 expression had significantly lower 5-year event-free survival (EFS) (18%, 95% CI 0-40%) as compared to those with low WT1 expression (68%, 95% CI 50-86%, P = 0.007). Multivariate analysis showed that pre-transplant WT1 level is the only significant prognostic factor for the difference in EFS. Our finding suggests that elevated WT1 gene expression before HSCT in paediatric AML predicts relapse and poor long-term EFS. A larger prospective study is warranted to compare the value of high WT1 expression and other markers of minimal residue disease in predicting clinical outcomes after HSCT.
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PMID:High WT1 gene expression before haematopoietic stem cell transplant in children with acute myeloid leukaemia predicts poor event-free survival. 1965 Aug 84


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