Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This report describes clinical, neuropathological and molecular genetic findings in a Swiss family with four brain tumours in only two generations. The neoplasms observed covered a wide range of biologic behaviour, from a slowly growing lesion already apparent at birth, to anaplastic astrocytoma in a young adult and glioblastomas at the age of less than 10 years. The only non-neural neoplasms in this family were a case of leukemia and an adrenocortical carcinoma. A germline deletion of codon 236 of the p53 tumour suppressor gene was identified as an underlying cause and detected in all affected family members. This mutation has not previously been reported as germline transmission or in sporadic tumours. The unusual accumulation of CNS tumours may be due to a certain organ-specific effect of this particular p53 mutation or it may reflect the specific genetic back-ground of this family.
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PMID:Familial brain tumour syndrome associated with a p53 germline deletion of codon 236. 776 87

There are two major classes of genes implicated in human tumorigenesis, the oncogenes and the tumour suppressor genes. In haematological malignancies most emphasis has been placed upon the recurring translocations in which the juxtaposition of two gene sequences has resulted in the activation of an oncogene. Chromosomal loss rather than translocation is the most frequent karyotypic abnormality in the myelodysplastic syndromes, a heterogeneous group of clonal malignant blood disorders characterised by dyshaematopoiesis and/or impaired maturation of haemopoietic cells with frequent evolution to acute leukaemia. Recent attention has focused on the loss of genetic material as a result of chromosomal monosomy or deletion in the myelodysplastic syndromes. The most frequently reported deletions in these myeloid syndromes are of chromosomes 5, 20 and 7. Deletions of chromosomes 11, 12, and 13, although more rarely observed, are also characteristics of the myelodysplastic syndromes. It is probable that the deleted chromosomal bands give the location for as yet unidentified myeloid specific tumour suppressor loci and there is considerable interest in the cloning of these genes. This review discusses the three most frequently observed deletions in MDS; 7q deletion, 5q deletion and 20q deletion taking into account recent evidence on the respective critical regions of gene loss and the role of candidate genes.
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PMID:Chromosomal deletions in myelodysplasia. 777 64

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.
Leukemia 1994 Nov
PMID:No evidence for microsatellite instability or consistent loss of heterozygosity at selected loci in chronic myeloid leukaemia blast crisis. 796 38

Hepatocyte growth factor (HGF) is a multi-functional molecule characterized as a mitogen, a motogen, a morphogen and a tumour suppressor. Little is known about cell types which produce HGF, so we analysed HGF production from cultured cell lines of haematopoietic cell lineage. A total of 138 human leukemia and virus-transformed cell lines were studied and the levels of HGF were measured by ELISA. A significant amount of HGF was detected in a variety of cell lines, including one T, four B, five non-T non-B, eight myeloid one erythroid and two EBV-transformed B cell lines. The amount of HGF spontaneously produced by three of the myeloid cell lines, KCL-22 (33.48 ng/ml), KG-1A (26.21 ng/ml), and KG-1 (18.81 ng/ml), is comparable to the amount produced by human embryonic lung fibroblast cells, known as high HGF-producers. Biological assays together with Western blot analyses verified that the immunoreactive HGF detected in the culture supernatant of haematopoietic cell lines had the same properties as authentic HGF. Moreover, HGF mRNA was detected in high HGF producers by Northern blot analysis. Our findings that lymphoid and myeloid cells function as a source of HGF may provide significant evidence for the involvement of haematopoietic cells in HGF-related morphogenesis and cell growth.
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PMID:Production of hepatocyte growth factor by human haematopoietic cell lines. 805 85

Mutations of the p53 tumour suppressor gene on chromosome 17p are a common genetic change in the malignant progression of many cancers. Here we report a case of a 71-year-old man with haematological, cytofluorimetric and cytochemical findings consistent with a 'de novo' M2 acute myeloid leukaemia (AML). A complex karyotype including a whole chromosome 17 and a t(17;?) (p11;?) was present in 8 of 10 metaphases of bone marrow cells. Southern blot analysis of the bone marrow DNA showed a specific loss of p53 gene in the AML cells. As far as we know, this is the first report of a deletion of both p53 alleles in leukaemia. The effect of the loss of p53 on the course of AML is discussed.
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PMID:Total loss of p53 DNA sequences in acute myeloid leukemia. 828 69

The recent finding that eight out of 10 multiple myeloma cell lines have p53 gene mutations prompted us to examine the p53 tumour suppressor gene in 25 non-related multiple myeloma patients. None of 19 patient bone marrow samples available for Southern blot analysis showed rearrangements in the p53 gene and only one patient showed loss of the p53 locus. DNA encompassing exons 5, 7, and 8, where p53 mutations commonly cluster, was amplified by PCR. Single-strand conformation polymorphisms of the PCR-amplified exon 5 region were detected in two patients. Direct sequencing of the mutant band revealed that one patient had a C to T transition at codon 138 (Ala to Val) and one patient had a G to C transversion at codon 139 (Lys to Asn). p53 mutations in germline cells in hereditary cancer syndromes predispose the family members to the development of malignancies. We therefore searched for p53 germline mutations in exons 5, 7, and 8 in the affected individuals from three families each with two multiple myeloma patients (these patients include three individuals from the non-related group mentioned above). Using Southern blotting, polymerase chain reaction/single-strand conformation polymorphism (PCR-SSCP) analysis and direct sequencing, no germline mutations were found. These results indicate that mutations in exons 5, 7, and 8 of the p53 gene are infrequent in multiple myeloma.
Leukemia 1993 Jul
PMID:Sporadic mutations of the p53 gene in multiple myeloma and no evidence for germline mutations in three familial multiple myeloma pedigrees. 832 Oct 49

Homozygous deletions of the cyclin-dependent kinase 4 (CDK4) inhibitor gene CDKN2 (p16, MTS1) have been demonstrated to occur frequently in human cancer cell lines of different origin. However, in most primary tumours the frequencies of CDKN2 deletions are not well defined. We studied primary samples of 100 patients with lymphoid leukaemias [B-lineage acute lymphoblastic leukaemia (ALL), n = 23; T-ALL, n = 7; B-cell chronic lymphocytic (B-CLL) or prolymphocytic (B-PLL) leukaemia, n = 50; T-CLL/T-PLL, n = 20] using fluorescence in situ hybridization (FISH) with eight overlapping cosmid clones covering the region on chromosome band 9p21 containing CDKN2. We did not observe any CDKN2 deletions in the 70 patients with chronic lymphoid leukaemias of B- or T-cell origin. Of the 23 patients with B-lineage ALL, one (4%) exhibited a CDKN2 deletion: in this patient, two clones were detected, one exhibiting a hemizygous and the other a homozygous deletion. On chromosome banding analysis, four patients with B-lineage ALL had a 9p aberration, whereas all CDKN2 copies were retained. In contrast, six of the seven (86%) patients with T-ALL exhibited CDKN2 deletions (homozygous, n = 4; hemizygous, n = 2). We conclude that hemizygous or homozygous deletions of the CDKN2 gene occur at high frequency in T-ALL and at low frequency in B-lineage ALL, supporting the role of this gene as a tumour suppressor, especially in T-ALL. However, from our data there is no evidence that CDKN2 is involved in the pathogenesis of chronic lymphoid leukaemias of B- or T-cell origin.
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PMID:CDKN2 gene deletion is not found in chronic lymphoid leukaemias of B- and T-cell origin but is frequent in acute lymphoblastic leukaemia. 854 31

Recent data suggest that homozygous deletion of the cyclin-dependent kinase 4 inhibitor gene (CDKN2), a putative tumour suppressor gene located on chromosome 9p21, represents a common genetic event in human cancer. As the molecular basis of the evolution of chronic myelogenous leukaemia (CML) into blast crisis remains largely unknown, we decided to investigate if the occurrence of similar deletions could represent one of the mechanisms underlying the disease progression. Whereas none of 22 chronic phase CML cases examined showed alterations, we found that 3/17 total blast crisis examined (18%) showed a homozygous deletion of the CDKN2 gene. The deletions were restricted to cases of lymphoid blast crisis, being present in 3/8 (40%) of the lymphoid and in none of the nine myeloid cases examined. The fact that the chronic phase DNA obtained at diagnosis in one of the cases lacks the homozygous deletion observed in blast crisis, suggests that the final deletion event took place concomitantly with the progression of the disease. Furthermore, the analysis of polymorphic regions on chromosome 9p21 flanking at both sides the CDKN2 gene, showed that deletions at 9p21 differ between cases and are characterized by a wide range of extensions. A concomitant search for a possible involvement of the p53 tumour suppressor gene in the same series of patients showed mutations of the gene and loss of heterozygosity at 17p only in myeloid blast crisis, suggesting the presence of distinct molecular pathways in the pathogenesis of lymphoid and myeloid blast crisis.
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PMID:Involvement of the cyclin-dependent kinase-4 inhibitor (CDKN2) gene in the pathogenesis of lymphoid blast crisis of chronic myelogenous leukaemia. 855 65

Retroviruses induce myeloid leukaemia in BXH-2 mice by the insertional mutation of cellular proto-oncogenes or tumour suppressor genes. Disease genes can thus be identified by proviral tagging through the identification of common viral integration sites in BXH-2 leukaemia. Here, we describe a new approach for proviral tagging that greatly facilitates the identification of BXH-2 leukaemia genes. Using this approach, we identify three genes whose expression is activated by proviral integration in BXH-2 leukaemias; Hoxa7, Hoxa9, and a Pbx1-related homeobox gene, Meis1. Proviral activation of Hoxa7 or Hoxa9 is strongly correlated with proviral activation of Meis1 implying that Hoxa7 and Hoxa9 cooperate with Meis1 in leukaemia formation. These studies provide the first genetic evidence that Pbx1-related genes cooperate with Hox genes in leukaemia formation and identify a number of new murine myeloid leukaemia genes.
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PMID:Cooperative activation of Hoxa and Pbx1-related genes in murine myeloid leukaemias. 856 41

The genes for acetylcholinesterase (ACHE) and butyrylcholinesterase (BCHE) are located within regions subject to non-random chromosomal abnormalities in the myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). Acetylcholinesterase is mapped to 7q22, within the critical deleted region presumed to contain a myeloid specific tumour suppressor gene. Butyrylcholinesterase is mapped to 3q26: abnormalities at this region are associated with sub-types of MDS and AML with thrombocytopenia, or with increased platelet counts. Both ACHE and BCHE have been implicated as playing a role in megakaryopoiesis and thrombopoiesis, and these genes have been observed to be co-amplified in acute myeloid leukaemia. Recent findings suggest a more significant role for the ACHE gene in haemopoiesis by regulating multipotent stem cell proliferation, and apoptosis in cells undergoing erythroid and myeloid differentiation. This led us to investigate gene copy-number alterations at these genes in MDS and AML. Samples were screened by slot-blot hybridization, and if changes were observed, by Southern blotting. A total of 42 samples from 31 de novo AML patients, 10 samples from eight cases of post-MDS AML and 85 samples from 67 MDS patients were analysed with probes for ACHE, BCHE, c-MYC, MDR-1 and globin control. Changes in ACHE and/or BCHE were observed in 9/31 de novo AML patients, and in 7/67 MDS patients: 1/37 cases of refractory anaemia (RA), 1/10 cases of refractory anaemia with excess blasts (RAEB) and 5/20 chronic myelomonocytic leukaemia (CMML) patients. The amplification events observed generated copy numbers no greater than 10, showed normal restriction patterns and had no clear correlation with megakaryopoiesis or thrombopoiesis. Loss of signal at the ACHE locus was observed: haploid signal intensity was seen in seven samples: one RA with thrombocytopenia, three CMML, one AML-M5a (no karyotypic abnormalities of chromosome 7), one AML-M4 (monosomy 7), and one case of AML-M7 (karyotype unknown). Homozygous deletion was observed at relapse of an additional patient with AML-M4. These data reinforce the possibility that ACHE may play a role as a myeloid tumour suppressor gene.
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PMID:Deletion of the acetylcholinesterase locus at 7q22 associated with myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). 863 18


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