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)

Continuous Wilms' tumor gene (WT1) expression is a typical feature of leukemic blasts in AML, ALL, and blast crisis CML patients. It is easily detectable by a variety of RT-PCR protocols, which differ mainly in their sensitivity. The nuclear WT1 protein can be found in blasts of approximately 50-60% of acute leukemia patients at diagnosis. Conversely, WT1 is only transiently expressed in normal hemopoiesis. Early CD34+ hemopoietic progenitors express WT1, whereas no WT1 mRNA transcripts can be found in mature blood cells and differentiation-induced committed CD34- progenitors. As a powerful complementary diagnostic tool, testing for WT1 expression can be helpful to discriminate between eosinophilic leukemia (EoL) patients and patients with idiopathic hypereosinophilic syndromes. Conflicting data about the usefulness of testing for WT1 expression to monitor minimal residual disease (MRD) in treated leukemia patients will be discussed. Finally, research strategies to circumvent shortcomings in detecting leukemia-associated WT1 expression will be outlined.
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PMID:Analysis of Wilms tumor gene (WT1) expression in acute leukemia patients with special reference to the differential diagnosis between eosinophilic leukemia and idiopathic hypereosinophilic syndromes. 1067

This study evaluated male gonadal function in long-term survivors of childhood cancer and assessed the suitability of offering sperm analysis to all those patients independently of the diagnosis and treatment received. A total of 43 survivors of acute lymphoblastic leukemia (21), acute myeloid leukemia (1), neuroblastoma (8), ganglioneuroblastoma (1), ganglioneuroma (2), Wilms' tumor (9), and mesoblastic nephroma (1) underwent sperm analysis at a mean age of 20.2 years, after a mean time off treatment of 13.6 years. Eight of the patients (19%) were azoospermic, 2 (5%) were severely oligo-asthenozoospermic, and only 16 (37%) were normozoospermic. A control group of healthy volunteers aged < or = 30 years included no azoospermic subjects, 7% severely oligo-asthenozoospermic, and 67% normozoospermic. Comparisons were also made with patients treated at our Human Reproductive Unit aged < or = 30 years (n = 373) whose percentages for the above parameters were 4, 9, and 42%, respectively. Cumulated cyclophosphamide dose and basal follicle-stimulating hormone (FSH) levels were identified as independent factors associated with azoospermia or severe oligo-asthenozoospermia. Azoospermic and severely oligo-asthenozoospermic survivors had significantly smaller mean testicular volume and higher basal FSH levels than the other survivors, but small testicles (sum of both testicular volume < or = 20 mL) and/or abnormally high basal FSH (> 10 mIU/mL) were present in only half of the azoospermic survivors. Male long-term survivors of childhood cancer constitute a high-risk subpopulation for altered sperm analysis. It seems justified to offer sperm analysis to all long-term survivors.
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PMID:Persistent altered spermatogenesis in long-term childhood cancer survivors. 1068 12

The curability of pediatric cancer has been improved to nearly seventy percent. This change has been achieved by refinements in treatment strategy and supportive care. More than seventy percent of patients with ALL can be cured by modern chemo-radiotherapy with reduced late effects. The stratification of the patients by risk factor, introduction of CNS prophylaxis, shortening of the duration of chemotherapy and intensification of the chemotherapy with agents such as HD-MTX have contributed to this remarkable success. Burkitt's lymphoma is a tumor for which the curability has improved from almost zero to ninety percent. With Wilms' tumor, clinical trials have been used to optimally refine the treatment strategy. The NWTS first compared the efficacy of combined VCR and Act-D with the single use of each drug. The difference was significant. The results of the systematic trials were then used to improve the survival rate of patients with Wilms' tumor from twenty to ninety percent and shorten the duration of chemotherapy to six months. On the other hand, tumors remain with which less than half of patients can survive for long. Advanced neuroblastoma and AML are typical such tumors. With these diseases, refinements in the treatment based on evidence derived from clinical trials have been insufficient. Further intensification of the treatment or novel approaches to control tumor growth are warranted for these diseases. In this article, I would like to describe the "standard" therapy for each tumor and the evidence on which improvements in those strategies have been based.
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PMID:[Evidence based chemotherapy for pediatric cancers]. 1070 Aug 90

Down Syndrome (DS) is associated with an increased incidence of malignancies, especially leukaemias. We came across 8 DS children presenting with malignancies and having trisomy 21 as the sole cytogenetic abnormality. Of these 8 DS cases, 4 presented with acute lymphocytic leukaemia, 2 with acute myeloid leukaemia and one case each with Hodgkin's disease and Wilms' tumour. There are contradictory reports regarding the distribution of myeloid versus lymphoid malignancies in DS children and their response to therapy. The exact mechanism by which patients with DS are predisposed to develop malignancies is unclear. However, presence of the extra chromosome no. 21 is presumed to disrupt the genetic balance which increases generalized susceptibility to genetic and environmental trauma. Furthermore, an increased methotrexate toxicity observed in these patients should also be taken into consideration in designing treatment for DS children with malignancies.
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PMID:Malignancies in Down syndrome. 1077 32

Wilms' tumor gene WT1 mRNA is a new marker of leukemic blast cells for AML, ALL, and CML. Minimal residual disease(MRD) of leukemia can be detected at frequencies as low as 1 in 10(3) to 10(4) normal bone marrow cells and 1 in 10(5) normal peripheral blood mononuclear cells by means of the quantitation of WT1 mRNA(WT1 assay) using reverse transcriptase-polymerase chain reaction. Thus, the WT1 assay makes it possible to rapidly assess the effectiveness of treatment and to evaluate the degree of eradication of leukemic cell in individual leukemia patients. Furthermore, WT1 assay can continuously assess the disease progression of myelodysplastic syndromes(MDS) and predict the evolution of MDS to overt AML within 6 months.
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PMID:[Genetic diagnosis of leukemia: diagnosis of relapse and complete remission, and prediction of leukemia onset]. 1080 19

The Wilms' tumor (WT1) gene participates in leukemogenesis and is overexpressed in most types of leukemia in humans. WT1 is also detectable in many types of lung, thyroid, breast, testicular, and ovarian cancers and melanoma in humans. Initial studies evaluated whether immune responses to murine WT1 can be elicited in mice. Murine and human WT1 are similar. Thus, mouse models might lead to resolution of many of the critical issues for developing WT1 vaccines. C57/BL6 (B6) mice were injected with synthetic peptides from the natural sequence of WT1 containing motifs for binding to major histocompatibility (MHC) class II molecules. Immunization induced helper T-cell responses specific for the immunizing WT1 peptides and antibody responses specific for WT1 protein. Screening of multiple murine cancer cell lines identified 2 murine cancers, TRAMP-C and BLKSV40, that "naturally" overexpress WT1. Immunization with MHC class I binding peptides induced WT1 peptide-specific cytotoxic T-lymphocyte (CTL) that specifically lysed TRAMP-C and BLKSV40. WT1 specificity of lysis was confirmed by cold target inhibition. No toxicity was noted by histopathologic evaluation in the WT1 peptide-immunized animals. WT1 peptide immunization did not show any effect on TRAMP-C tumor growth in vivo. Immunization of B6 mice to syngeneic TRAMP-C elicited WT1-specific antibody, demonstrating that WT1 can be immunogenic in the context of cancer cells. To evaluate whether WT1 might be similarly immunogenic in humans, serum from patients with leukemia was evaluated for pre-existing antibody responses. Western blot analyses showed WT1-specific antibodies directed against the N-terminus portion of the WT1 protein in the sera of 3 of 18 patients with acute myeloid leukemia (AML). (Blood. 2000;96:1480-1489)
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PMID:Immunity to WT1 in the animal model and in patients with acute myeloid leukemia. 1094 95

Interleukin-12 (IL-12) has potent antitumor activities. We examined whether IL-12 enhanced the cytotoxicity of peripheral blood mononuclear cells (PBMNC) and decreased leukemia cells in 30 patients with leukemia or myelodysplastic syndromes (MDS): 12 acute myeloid leukemia (AML) (five in complete remission (CR) and seven in non-CR); six chronic myeloid leukemia (CML); and 12 MDS (three refractory anemia (RA), eight RA with excess of blasts and one chronic myelomonocytic leukemia). PBMNC from patients and five healthy volunteers were cultured at 5 x 10(5)/ml parallel with or without 100 units/ml of IL-12 for 3 days. Cytotoxicity of PBMNC against K562 cells was assessed by flow cytometry. To quantify the amount of leukemia cells, WT1 mRNA was measured by competitive reverse transcription polymerase chain reaction (RT-PCR), since WT1 mRNA is considered as a marker of minimal residual disease (MRD) in leukemia or MDS. The cytotoxicity of non-IL-12-treated PBMNC of 30 patients was 13.4+/-9.3% at the effector to target (E:T) ratio of 20:1, and significantly lower than that of normal subjects (25.7+/-8.4%). The cytotoxicity increased to 30.6+/-17.9% in the IL-12-treated PBMNC. WT1 mRNA in PBMNC of five healthy volunteers was less than 10(3) copies/microg of total RNA. Following the 3-day IL-12 treatment, mean WT1 mRNA of PBMNC was reduced from 10(4.8) to 10(4.2) copies/microg of total RNA in six CML patients, from 10(5.4) to 10(4.8) copies/microg in 12 MDS patients and from 10(5.0) to 10(4.2) copies/microg in five AML patients in CR, but not reduced in five of seven AML in non-CR. These results showed that IL-12 significantly enhanced PBMNC cytotoxicity and decreased the quantity of leukemia cells in PBMNC of most patients with MDS, CML and AML in CR. IL-12 might be of considerable benefit in the elimination of MRD in patients with hematological malignancies.
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PMID:In vitro IL-12 treatment of peripheral blood mononuclear cells from patients with leukemia or myelodysplastic syndromes: increase in cytotoxicity and reduction in WT1 gene expression. 1099 11

WT1 is an oncogenic protein expressed by the Wilms' tumor gene and overexpressed in the majority of acute myelogenous leukemias (AMLs) and chronic myelogenous leukemias (CMLs). The current study analyzed the sera of patients with AML and CML for the presence of antibodies to full-length and truncated WT1 proteins. Sixteen of 63 patients (25%) with AML had serum antibodies reactive with WT1/full-length protein. Serum antibodies from all 16 were also reactive with WT1/NH2-terminal protein. By marked contrast, only 2 had reactivity to WT1/COOH-terminal protein. Thus, the level of immunological tolerance to the COOH terminus may be higher than to the NH2 terminus. The WT1/COOH-terminal protein contains four zinc finger domains with homology to other self-proteins. By implication, these homologies may be related to the increased immunological tolerance. Results in patients with CML were similar with antibodies reactive to WT1/full-length protein detectable in serum of 15 of 81 patients (19%). Antibodies reactive with WT1/NH2-terminal protein were present in the serum of all 15, whereas antibodies reactive with WT1/COOH-terminal protein were present in only 3. By contrast to results in leukemia patients, antibodies reactive with WT1/full-length protein were detected in only 2 of 96 normal individuals. The greater incidence of antibody in leukemia patients provides strong evidence that immunization to the WT1 protein occurred as a result of patients bearing malignancy that expresses WT1. These data provide further stimulus to test therapeutic vaccines directed against WT1 with increased expectation that the vaccines will be able to elicit and/or boost an immune response to WT1.
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PMID:WT1-specific serum antibodies in patients with leukemia. 1130 Apr 70

The measurement of Wilms' tumor gene (WT1) mRNA levels by reverse transcriptase-polymerase chain reaction (RT-PCR) is useful in detecting minimal residual disease (MRD) in leukemia patients. In the present study, we quantified the level of WT1 mRNA in the peripheral blood and bone marrow of patients with acute myelocytic leukemia (AML) at initial onset, remission and recurrence by the use of nucleic acid sequence based amplification (NASBA), and then ascertained the clinical usefulness of this method. At initial onset, the level of WT1 mRNA in the peripheral blood was above 10(3) copies/microgram and that in the bone marrow was above 10(4) copies/microgram. The level of WT1 mRNA was decreased in cases where therapy resulted in complete remission, but it was abnormally high in recurring cases. In AML (M3) patients, the relationship between the level of WT1 mRNA and the expression of the PML-retinoic acid alpha receptor (RAR alpha) gene, assessed by fluorescence in situ hybridization (FISH), was investigated. When leukemia was in remission hematologically, the PML-RAR alpha gene was negative and the level of WT1 mRNA decreased. These findings suggest that the quantification of WT1 gene expression by competitive NASBA is useful in assessing therapeutic effects and detecting MRD.
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PMID:Quantification of WT1 mRNA by competitive NASBA in AML patients. 1150 93

P-glycoprotein (P-gp)/multi-drug resistance 1 (MDR1) gene is recognized to be, at least in part, responsible for the refractoriness to chemotherapy of leukemia. The transcriptional mechanism of MDR1 gene is largely unknown. However, recent reports have clarified that early growth response 1 gene (Egr1) positively regulates MDR1 transcription, while Wilms' tumor suppressor gene (WT1) does negative regulation of MDR1 gene expression in 12-O-tetradecanoylphorbol-13-acetate treated K562 cells. In addition, Egr1 and WT1 are structurally related transcription factors and bind to quite similar DNA sequences. Our study of mRNA expression profile of Egr1, WT1 and MDR1 in fresh AML samples demonstrated that there are disease-specific patterns. Egr1 mRNA was frequently and strongly expressed in monocytic leukemia cells, especially in AML M4 cells. WT1 mRNA was undetectable in t(8;21) AML cells. mRNA expression of MDR1 was frequent in AML M1 and t(8;21) AML cells, in which the expression level was highest in AML M1 and was low in monocytic leukemia (M4 and M5). Then, expression level of MDR1 was inversely correlated with Egr1. By liquid culture of leukemia cell lines and fresh AML cells with the addition of all-trans retinoic acid (ATRA), modulation of P-gp/MDR1 and Egr1 was observed and the pattern of modulation was divided into four groups: (1) blastic AML type, in which distinct expression of P-gp/MDR1 and CD34 was not influenced by ATRA; (2) t(8;21)AML type, in which P-gp/MDR1 expression was augmented by ATRA, while CD34 was kept high; (3) AML M3 type, in which P-gp/MDR1 expression was reduced with granulocytic differentiation by ATRA; (4) monocytic AML type, in which P-gp/MDR1 expression was augmented by ATRA, while CD34 expression decreased, and strong Egr1 expression was downregulated just prior to the augmentation of P-gp/MDR1 expression. WT1 expression was not influenced by the addition of ATRA in each group. Previous reports have suggested that P-gp/MDR1 plays an important role in resistance to chemotherapy, and is recognized as one of the stem cell marker. However, P-gp/MDR1 expression augmented by ATRA, which was observed in monocytic AML, was recognized as a functional molecule of mature monocyte/macrophage, because CD34 expression decreased and CD13 expression increased by ATRA. Finally, expression of P-gp/MDR1 in monocytic leukemia, which was functionally confirmed by Rh123 efflux study, was thought to be closely related to the characteristic modulation of Egr1 expression by ATRA.
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PMID:Augmented expression of P-gp/multi-drug resistance gene by all-trans retinoic acid in monocytic leukemic cells. 1173 1


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