Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The WT 1 gene has been isolated as a tumor suppressor gene of Wilms' tumor. Using reverse transcriptase-polymerase chain reaction (RT-PCR), relative levels of the WT 1 gene expression was examined in 87 patients with acute leukemia, 25 with chronic myelogenous leukemia (CML), and 24 with non-Hodgkin's lymphoma (NHL). Significant levels of the WT 1 gene were expressed in all leukemia patients, and for CML the levels increased as the clinical phase progressed. No point mutations were found in the WT 1 gene when samples from 15 acute leukemia patients were subjected to PCR single-strand conformation polymorphism analysis. In striking contrast to acute leukemia, the levels of WT1 gene expression for NHL were significantly low or even undetectable. The levels of WT 1 gene expression inversely correlated with the prognosis of acute leukemia. The quantification of the WT 1 gene expression made it possible to detect minimal residual disease (MRD) in acute leukemia regardless of the presence of absence of tumor-specific DNA markers. Simultaneous monitoring of MRD by RT-PCR using primers for specific DNA markers in four patients (two AML-M3 with PML/RAR-alpha, one AML-M2 with AML1/ETO, and one CML with bcr/abl) detected MRD comparable to that obtained from quantitation of WT 1 gene expression. In a patient with acute promyelocytic leukemia, the limits of leukemic cell detection by RT-PCR using either WT 1 or PML/RAR-alpha gene primers were 10(-3)-10(-4) and 10(-4) for bone marrow, and 10(-5) and 10(-4) for peripheral blood, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[WT 1 and leukemia]. 764 50

The WT1 gene encoding a zinc finger polypeptide is a tumor suppressor gene that plays a key role in the carcinogenesis of Wilms' tumor. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to examine relative levels of WT1 gene expression (defined in K562 cells as 1.00) in 45 patients with acute myelogenous leukemia (AML), 22 with acute lymphocytic leukemia (ALL), 6 with acute mixed lineage leukemia (AMLL), 23 with chronic myelogenous leukemia (CML), and 24 with non-Hodgkin's lymphoma. Significant levels of WT1 gene were expressed in all leukemia patients and for CML the levels increased as the clinical phase progressed. In striking contrast with acute leukemia, the levels of WT1 gene expression for NHL were significantly lower or even undetectable. Clear correlation was observed between the relative levels of WT1 gene expression (< 0.6 v > or = 0.6) and the prognosis for acute leukemia (AML, ALL, and AMLL). Patients with less than 0.6 levels had significantly higher rates of complete remission (CR), disease-free survival, and overall survival than those with > or = 0.6 levels, whereas CR could not be induced in any of the 7 patients with acute leukemia having greater than 1.0 levels of WT1 gene expression. The quantitation of the WT1 gene expression made it possible to detect minimal residual disease (MRD) in acute leukemia regardless of the presence or absence of tumor-specific DNA markers. Continuous monitoring of the WT1 mRNA was performed for 9 patients with acute leukemia. In 4 patients, MRD was detected 2 to 8 months before clinical relapse became apparent. In 2 other patients, the WT1 mRNA gradually increased after discontinuation of chemotherapy. No MRD was detected in the remaining 3 patients with AML who received intensive induction and consolidation therapy. Simultaneous monitoring of MRD by RT-PCR using primers for specific DNA markers in 3 patients (2 AML-M3 with PML/RAR alpha, and 1 AML-M2 with AML1/ETO) among these 9 patients detected MRD comparable with that obtained from quantitation of WT1 gene expression. In a patient with acute promyelocytic leukemia, the limits of leukemic cell detection by RT-PCR using either WT1 or promyelocytic leukemia/retinoic acid receptor-alpha gene primers were 10(-3) to 10(-4) and 10(-4) for bone marrow, and 10(-5) and 10(-4) for peripheral blood, respectively. Therefore, we conclude that WT1 is a new prognostic factor and a new marker for the detection of MRD in acute leukemia.
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PMID:WT1 as a new prognostic factor and a new marker for the detection of minimal residual disease in acute leukemia. 794 79

The aim of the present study was to investigate loss of heterozygosity (LOH) or microsatellite instability in chronic myeloid leukaemia (CML) blast crisis at genomic locations which are known or postulated to harbour tumour suppressor genes. We studied 48 patients in blast crisis of myeloid (n = 31), lymphoid (n = 15), megakaryocytic (n = 1), or mixed lineage (n = 1) phenotype by comparing constitutional DNA extracted from buccal epithelial cells or chronic phase leucocytes with DNA obtained from blast crisis leucocytes. Twelve variable number tandem repeat loci from six different chromosomes were amplified by polymerase chain reaction using labelled primers, and fractionated on polyacrylamide gels. After autoradiography, length as well as intensity of the amplified products were compared between constitutional and blast crisis samples. LOH was scored as complete, partial or none in informative patients. Complete LOH was found in one patient at 8p22 and another at 13q14; partial LOH was detected in three patients at 11p13 and/or 11p15. No LOH was found at 6q27, 8p21, 18q21, 22q11-12 and 22q13 in any patient. Furthermore, no consistent difference in allelic length was observed in 517 paired amplifications indicating no microsatellite instability. We conclude that the Rb gene at 13q14, the Wilms tumour gene at 11p13, the DCC gene at 18q21, the neurofibromatosis 2 gene at 22q11-13 and uncloned tumour suppressor genes at 6q27, 8p21-22 and 11p15, as well as genes responsible for microsatellite instability, are unlikely to be involved in the progression of CML to blast crisis in the majority of patients.
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PMID:No evidence for microsatellite instability or consistent loss of heterozygosity at selected loci in chronic myeloid leukaemia blast crisis. 796 38

The therapeutic effects of Factor XIII (F XIII) concentrate against drug-induced hemorrhagic cystitis (HC) was investigated. HC occurred in 4 children with malignant disease during anti-cancer chemotherapy. Two (CML and T-ALL) of 4 patients developed HC after the administration of high dose cyclophosphamide as conditioning for allo bone marrow transplantation or peripheral blood stem cell autografts, and the other 2 patients (rhabdomyosarcoma, Wilm's tumor) developed HC after the administration of ifosfamide for relapse. When F XIII concentrate at a dose of 20 to 230 U/kg was administrated immediately after the onset of HC, the symptoms, i.e., bladder irritability and macrohematuria disappeared within a few days. The F XIII serum levels of those patients were low (27-57%), and the levels increased (63-230%) after administration of F XIII concentrate. The two patients with relapsed solid tumor showed no symptoms of HC during subsequent ifosfamide treatment when F XIII concentrate was administrated to maintain a normal F XIII range. These results suggest that the administration of F XIII concentrate may be useful for the prophylaxis and treatment of drug-induced HC in patients with a low F XIII level.
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PMID:[The clinical effect of factor XIII on drug-induced hemorrhagic cystitis]. 815 49

Oncogenes are genes associated with causation of cancer. They were originally associated with the ability of retroviruses to cause tumors in animals. These viral oncogenes (V-onc) have their cellular counterparts (C-onc) called Proto oncogenes. Function of Proto oncogenes is to maintain cellular growth and development. Activation of these proto-oncogenes can occur due to mutation which leads to uncontrolled cell growth. The Proto oncogenes can be grouped into different categories based on their protein products, i.e. protein kinases, growth factors, growth factor receptors, and DNA binding proteins. There are also genes that normally suppress malignant transformation and these are called anti oncogenes. Loss of their suppressor activity leads to unimpeded growth. Oncogene abnormalities are seen in pediatric leukemias, lymphomas, and various solid tumors. Anti oncogenes are associated with retinoblastoma (Rb gene), Wilms' tumor, rhabdomyosarcoma and neuroblastoma, etc. Identification of these abnormalities have diagnostic, prognostic and therapeutic implications. The utility of oncogenes in classification of human cancer and monitoring cancer therapy is quite clear, but the future of these for therapeutic interventions remains uncertain. Role of c-abl oncogene in chronic myeloid leukemia (CML), bcl-2, in lymphomas, N-myc in neuroblastomas and retinoblastoma (Rb) gene in retinoblastomas is well understood and used in designing proper therapeutic approaches. Since oncogenes also control normal cellular function, their use for therapy may be limited by the amount of damage to normal cells. Their maximum therapeutic benefit may be realized only when used in combination with other modalities.
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PMID:Oncogenes: present status. 824 94

Wilms' tumor (WT) is a pediatric malignancy that occurs in embryonic kidney. Recently, a putative Wilms' tumor gene (WT1), located on chromosome 11p13, was isolated and characterized. We found constitutive expression of WT1 mRNA in eight out of 22 hematopoietic cell lines and seven out of 26 clinical samples which were derived from patients with various types of hematologic malignancies. WT1 mRNA was detected in four out of six myeloid cell lines, four out of 10 cases of acute myelocytic leukemia, three out of 15 lymphoid cell lines, one out of nine cases of lymphoid malignancies, and one out of six cases of chronic myelocytic leukemia in accelerated phase and blast crisis. One unclassified hematopoietic cell line and a case of myelodysplastic syndrome also expressed WT1 mRNA. No mutations were detectable in the cell lines by Southern blot analysis and a polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis in the four zinc finger domains of the WT1 gene. These results suggest that WT1 gene is expressed in several types of immature lymphoid or myeloid leukemia cells possibly without alterations of the WT1 gene.
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PMID:Expression of the candidate Wilm's tumor gene, WT1, in human leukemia cells. 832 Oct 47

We have previously reported expression of WT1 in acute leukemia. To elucidate its biological significance, we examined the effect of the suppression of the WT1 expression by WT1 antisense oligomers on the growth of the leukemic cells expressing WT1. When 20 different WT1 antisense (AS) oligomers covering from the 5' cap sites of the WT1 gene to the 3' end were examined for the inhibitory effect on the growth of K562 cells expressing WT1, four WT1 AS oligomers inhibited the cell growth, whereas WT1 sense and random sequence oligomers had no effect on the cell growth of K562. Moreover, WT1 AS oligomers significantly inhibited the growth of the clonogenic cells of fresh leukemic cells in six of 14 patients with acute myeloid leukemia, in one of two patients with chronic myelogenous leukemia (CML) chronic phase, and in one of one patient with CML blastic crisis. However, these oligomers did not inhibit normal colony-forming unit-granulocyte-macrophage. Western blot analysis clearly demonstrated the significant reduction in the WT1 protein levels in the K562 and fresh leukemic cells that were treated with the WT1 AS oligomers, confirming that the inhibitory effect of the WT1 AS oligomers on the cell growth operates via the reduction in the WT1 protein levels. These results show that WT1 plays an important role in leukemogenesis.
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PMID:Growth inhibition of human leukemic cells by WT1 (Wilms tumor gene) antisense oligodeoxynucleotides: implications for the involvement of WT1 in leukemogenesis. 863 7

The response of the CML-BC cell line, K562, the myelomonocytic cell line MM6 and the promyelocytic leukaemia cell line HL-60, to a 15 mer WT1 antisense oligonucleotide, targeted to the translation initiation site of the WT1 mRNA was examined. K562 cells exposed to 0.4 microM antisense oligonucleotide showed markedly reduced proliferation which was associated with reduced cell viability. Sense, scrambled and mutant antisense oligonucleotides had no effect on the proliferation of K562 cells. MM6 cells exposed to 0.4 microM antisense oligonucleotide also showed significantly reduced cellular proliferation which was also accompanied by loss of cell viability. In the K562 and MM6 antisense cultures that exhibited reduced cell viability, both DNA fragmentation and morphological features consistent with apoptosis could be identified. In contrast the growth of HL-60 cells was unaffected by exposure to 0.4 microM antisense oligonucleotide. In each of the cell lines examined, WT1 antisense oligonucleotide abrogated WT1 protein expression, and analysis of WT1 coding sequence in these cells showed that no oncogenic point mutations in the gene were present. We propose therefore that in some myeloid leukaemia cell lines, the expression of a normal WT1 protein is necessary for cell proliferation and that it plays a role in maintaining the viability of some leukaemia cells.
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PMID:A WT1 antisense oligonucleotide inhibits proliferation and induces apoptosis in myeloid leukaemia cell lines. 864 91

Thirty-one patients (27 with acute myeloid leukemia [AML], 2 with acute lymphocytic leukemia [ALL], and 2 with acute mixed lineage leukemia [AMLL]) treated with conventional chemotherapy (CHT) and 23 patients (13 AML, 5 ALL, and 5 with chronic myeloid leukemia [CML]) treated with allogeneic bone marrow transplantation (BMT) were monitored for WT1 expression levels in BM and peripheral blood (PB) by reverse transcriptase-polymerase chain reaction over a long-term period (mean, 29 months for CHT and 24 months for BMT). Sixteen of the patients in the CHT group and 3 in the BMT group who had achieved complete remission suffered clinical relapse. In 10 of these patients, WT1 expression that had returned to normal BM levels (< 10(-3); the WT1 expression level of K562 cells was defined as 1.0) after complete remission (CR) either gradually or rapidly increased again to abnormal levels 1 to 18 months (mean, 7 months) before clinical relapse became apparent. In another 9 patients, WT1 expression never returned to normal BM levels even after CR and the subsequent relapse was accompanied by a rapid increase in WT1 expression to levels higher than 10(-2) (10(-3) levels in PB). On the other hand, the remaining 35 patients (15 CHT and 20 BMT) maintained their CR. In 29 of these patients (11 CHT and 18 BMT), WT1 expression either gradually or rapidly decreased to normal BM levels, whereas in the other 6 (4 CHT and 2 BMT), low or very low levels of WT1 mRNAs (10(-3) to 10(-2) in BM and 10(-5) to 10(-3) in PB) remain detectable, but without any clinical signs of relapse. A clear correlation was found to exist between the minimal residual disease (MRD) detected in the paired BM and PB samples for all types of leukemias (AML, ALL, and CML), with MRD in PB being approximately one-tenth of that in BM. WT1 quantitation of 168 paired BM and PB samples showed that PB samples were superior to BM samples for the detection of MRD. We conclude that monitoring of WT1 expression levels in BM and PB makes it possible to rapidly assess the effectiveness of individual treatment and diagnose clinical relapse in the early stage for all leukemia patients regardless of the presence or absence of tumor-specific DNA markers.
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PMID:Long-term follow-up of minimal residual disease in leukemia patients by monitoring WT1 (Wilms tumor gene) expression levels. 882 48

To determine if mutations of the Wilms' tumor predisposing gene (WT1) are associated with haematological malignancies, we have investigated 65 cases of acute leukaemia, including 39 patients in blast crisis of chronic myeloid leukaemia (CML), by amplification of WT1 exons 7, 8 and 9 followed by single-strand conformation polymorphism analysis. WT1 transcripts were detected by RT-PCR in all samples. An exon 7 silent polymorphism (A-->G; Arg 313) was identified in 17 individuals, 5 of whom were homozygous, but no other lesions were found. In 1 sample from a patient with acute lymphoblastic leukaemia a smaller size transcript missing exon 9 was detected; a similar abnormality has been described previously in a patient with Wilms' tumour and the resultant protein shown to act in a dominant-negative manner. No mutations of the exon 9 donor or acceptor splice sites were found in this patient and the basis of the abnormal transcript remains obscure. We conclude that dominant-negative mutations of the zinc finger region of the WT1 gene are uncommon in CML blast crisis. Abnormalities of this gene may, however, contribute to a small proportion of cases of de novo acute leukaemia.
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PMID:Dominant-negative mutations of the Wilms' tumour predisposing gene (WT1) are infrequent in CML blast crisis and de novo acute leukaemia. 922 90


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