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)

Microsatellites are unique highly polymorphic and informative genetic markers dispersed in the human genome. Their detection by PCR is rapid and a wide variety of DNA sources including archival material are available for diagnostic purposes. Microsatellite typing of haematological neoplasms may be applied to the search for loss of heterozygosity at loci possibly harbouring tumour suppressor genes, for example in acute lymphoblastic leukaemia. The technique may detect submicroscopical chromosomal deletions which are not visible in the leukaemic karyotype. RER+ tumours exhibiting microsatellite instability appear to be rare among haematological cancers with the possible exception of lymphoid tumours in immunosuppressed patients and lymphomas derived from mucosa-associated lymphoid tissue. An X-chromosomal microsatellite near the human androgen receptor gene (HUMARA) may be used for clonal X-inactivation analysis. Microsatellites therefore represent a collection of powerful genetic markers suitable to tackle questions relevant to basic research and clinical problems in leukaemia and lymphoma.
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PMID:Microsatellite markers in leukaemia and lymphoma: comments on a timely topic. 949 99

Aberrant DNA methylation has been observed consistently in many human tumours, in particular in the CpG islands of tumour suppressor genes, but the underlying mechanism of these changes remains unclear. To determine whether DNA methyltransferase expression is increased in leukaemia, we developed a standardised competitive RT-PCR assay to measure the level of DNA methyltransferase transcripts. Using this assay on bone marrow RNA samples from 12 patients with acute leukaemia, we observed a 4.4-fold mean increase in the level of DNA methyltransferase mRNA compared with normal bone marrow. These results support but do not prove the hypothesis that an increase in DNA methyltransferase activity is associated with malignant haematological diseases and may constitute a key step in carcinogenesis.
Leukemia 1998 Mar
PMID:Increased DNA methyltransferase expression in leukaemia. 952 24

Bax suppresses tumorigenesis in a mouse model system and Bax-deficient mice exhibit lymphoid hyperplasia suggesting that BAX functions as a tumour suppressor in human haemopoietic cells. We examined BAX expression in 20 cell lines derived from human haemopoietic malignancies and consistent with a potential tumour suppressor function, identified two cell lines, DG75 (a Burkitt lymphoma cell line) and Jurkat (a T-cell leukaemia line), which lacked detectable BAX expression. Apoptosis of DG75 cells induced by low serum or ionomycin was significantly delayed relative to similar Burkitt lymphoma cell lines with normal BAX levels. Although DG75 and Jurkat cells expressed several BAX RNA species including the prototypical BAX alpha RNA, the absence of BAX protein was due to single base deletions and additions in a polyguanine tract within the BAX open reading frame. These frameshift mutations result in premature termination of translation and have recently also been identified in some colon cancers with microsatellite instability. Although mismatch repair defects are not considered a common feature of haemopoietic malignancies, DG75 and Jurkat cells had widespread microsatellite instability and did not express detectable levels of MSH2. In Jurkat cells, lack of MSH2 expression was due to a point mutation in exon 13 of MSH2 resulting in premature termination of translation. Our results suggest that a pathway linking mismatch repair defects, BAX tumour suppressor frameshift mutations and resistance to apoptosis may be a key feature of some lymphomas and leukaemias.
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PMID:BAX frameshift mutations in cell lines derived from human haemopoietic malignancies are associated with resistance to apoptosis and microsatellite instability. 958 78

The most frequent structural chromosome abnormality in chronic lymphocytic leukaemia (CLL) is deletion at chromosome 13q14. Studies with Southern blot hybridisation have revealed deletions in the region located telomeric of the retinoblastoma gene in more than 40% of cases. The highest frequency of homozygous deletions has been found at the D13S319 locus and it is likely that a new tumour suppressor gene is located close to this region. We have analysed deletions in the D13S319 region in 20 selected CLL patients using conventional cytogenetic analysis, fluorescence in situ hybridisation (FISH) and Southern blot hybridisation. FISH and Southern hybridisation are equally efficient in detecting deleted clones in our study. However, FISH analysis indicate that subclones with different numbers of alleles in the D13S319 region can exist simultaneously. The cytogenetic analyses confirm that clones with different chromosomal abnormalities can occur in patients with CLL and that 13q14 deletions can be limited to one of these subclones. Furthermore, the FISH analyses show that trisomy 12 and deletion of 13q14 can occur in the same cell clone. Finally, our study confirms that mitogen stimulation of peripheral blood cells from CLL patients before FISH analysis may result in a sharp increase in normal appearing cells, which can hide leukaemic clones with deletions in the D13S319 region.
Leukemia 1998 May
PMID:A FISH cosmid 'cocktail' for detection of 13q deletions in chronic lymphocytic leukaemia--comparison with cytogenetics and Southern hybridization. 959 68

A search was initiated towards the localization of novel mutated tumour suppressor genes that may be involved in adult leukaemia. For this purpose, we measured the occurrence of loss of heterozygosity (LOH) in nine patients with acute B-lineage leukaemia (ALL) and one with undifferentiated leukaemia (AUL). Eight leukaemias exhibited a diploid karyotype. For each patient, PCR products of 130 polymorphic microsatellite markers, located in subtelomeric areas of every autosomal chromosome arm were analysed to visualize LOH events resulting from reduplication of a single mutated chromosome or from mitotic recombination. These kinds of LOH events contribute most to LOH in model systems but cannot be detected by classical cytogenetic techniques. By comparing allelic PCR products in tumour cells with those in normal cells, LOH was found in tumour cells of one ALL patient at 9p which harbours the known p16INK4A tumour suppressor gene. In the AUL patient, however, LOH was detected at the telomeres of 4q and 21q, suggesting that these sites may contain novel tumour suppressor genes specifically involved in this form of leukaemia. In the DNA of tumour cells from eight out of 10 patients no LOH was detected. This is in contrast with the general assumption that LOH is a frequent phenomenon in ALL. However, some markers at telomeric regions of chromosomes were already homozygous in the control T-cells of several patients. For instance, we found in the DNA of control cells from one patient five consecutive microsatellites on 9p up to 9p43 which were homozygous and in three other patients homozygosity was observed in band 8q24, which includes the MYC gene. These observations indicate that LOH events already are present in non-cancerous putative stem cells and that mitotic recombination may be a very early event in leukaemogenesis.
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PMID:A search for novel tumour suppressor genes for adult acute leukaemia by allelotyping at sub-telomeric chromosomal regions. 968

The CD95 system plays an important role in lymphocyte homeostasis, has been implicated in the development of lymphoid malignancies, exerts a tumour suppressor function, and contributes to drug-induced cytotoxicity. We hypothesized that mutations of CD95 may occur in childhood B-lineage acute lymphoblastic leukaemia (ALL), a disease known for its constitutive resistance towards CD95-mediated apoptosis. We investigated 32 primary B-lineage ALL of childhood and five B-lineage ALL cell lines. All primary leukaemias expressed CD9 5 and bcl-2 to a variable degree. Most of the leukaemias were resistant towards CD95-mediated apoptosis. However, using SSCP analysis, no mutations in the coding and proximal promoter region could be detected. We conclude that the resistance towards CD95-mediated apoptosis observed in most de novo B-lineage ALL is not caused by mutations of the CD95 death receptor.
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PMID:Mutation analysis of CD95 (APO-1/Fas) in childhood B-lineage acute lymphoblastic leukaemia. 972 99

Recently, a tumour susceptibility gene, TSG101, has been identified at chromosome 11p15. A large intragenic deletion of this gene has been demonstrated in primary breast tumours. To evaluate the role of the TSG101 gene in leukaemia, bone marrow and/or peripheral blood from 68 acute myeloid leukaemia patients, five haemopoietic cell lines (HL60, U937. Raji, KG-1, K562) and 30 normal controls were analysed by reverse transcription of the TSG101 mRNA, followed by PCR amplification and sequencing of the products. The results showed aberrant TSG101 transcripts in 24/68 (35%) acute myeloid leukaemia (AML) patients, all of the cell lines (100%) and 3/30 (10%) normal controls. Our study indicated that the abnormal transcripts may have resulted from aberrant RNA splicing as evidenced by these aberrant transcripts. Also, normal full-length transcripts were present in all specimens examined. The aberrant transcript occurred more frequently in the AML and cell lines. However, because aberrant transcripts of TSG101 were also found in the normal controls, the role of TSG101 as a tumour suppressor gene should be evaluated carefully.
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PMID:Aberrant TSG101 transcripts in acute myeloid leukaemia. 972 3

The PML gene of acute promyelocytic leukaemia (APL) encodes a cell growth and tumour suppressor, however, the mechanisms by which PML suppresses tumorigenesis are poorly understood. We show here that Pml is required for Fas- and caspase-dependent DNA-damage-induced apoptosis. We also found that Pml is essential for induction of programmed cell death by Fas, tumour necrosis factor alpha (TNF), ceramide and type I and II interferons (IFNs). As a result, Pml-/- mice and cells are protected from the lethal effects of ionizing radiation and anti-Fas antibody. Pml is required for caspase 1 and caspase 3 activation upon exposure to these stimuli. The PML-RAR alpha fusion protein of APL renders haemopoietic progenitor cells resistant to Fas-, TNF- and IFN-induced apoptosis with a lack of caspase 3 activation, thus acting as a Pml dominant-negative product. These results demonstrate that Pml is a mediator of multiple apoptotic signals, and implicate inhibition of apoptosis in the pathogenesis of APL.
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PMID:PML is essential for multiple apoptotic pathways. 980 33

Homozygous deletion of the p16 tumour suppressor gene (at frequencies ranging from 14% to 29%) have been implicated in the pathogenesis of acute lymphoblastic leukaemia (ALL) by several studies. We investigated the prevalence of this deletion in a group of 46 Arab patients with common ALL. Deletion of p16 was assessed in a multiplex PCR which amplified a 405 bp fragment from exon 2 of the p16 gene, and a 242 bp fragment of the ApoE lipoprotein gene which served as an internal control. Homozygous deletion of p16 in tumour cells could be readily detected in samples containing >75% blasts. Surprisingly, none of the cases in our study showed homozygous deletion of the p16 gene. We also investigated the possibility of other genetic alterations in the p16 gene or mutation in the p21 and CDK4 (not previously reported in ALL) genes which are part of the same signal transduction pathway. A heterozygous G --> A transition at nucleotide position 273 of the p16 gene was present in one patient, but did not result in an amino acid change. A C --> A transversion at codon 88 of the p21 gene, which results in replacement of a phenylalanine with a leucine at position 63, was detected in one patient. In another patient a G --> C transversion in exon 2 at codon 82 (5'-untranslated region of the CDK4 gene) was detected. Results of this study showed mutation of p16, p21 or CDK4 to be rare events in Arab ALL patients.
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PMID:Mutation of p16, p21 or cyclin dependent kinase 4 is rare in acute lymphoblastic leukaemia. 982 21

Ataxia-telangiectasia (A-T) is a multisystem recessive disease characterized by cerebellar ataxia, oculocutaneous telangiectasias, immunodeficiency and increased risk of cancer. The ATM gene, responsible for A-T, was recently cloned at human chromosome band 11q22-23, a region of frequent alterations in childhood acute lymphoblastic leukaemia (ALL). Children with A-T frequently develop T-ALL. We investigated 18 T-ALL samples for ATM mutations and loss of heterozygosity (LOH) at the ATM locus. No mutations of ATM were found within the coding region in the 18 T-ALL samples, and LOH at the ATM locus was detected in three. The ATM gene appears to be an infrequently altered tumour suppressor gene in childhood T-ALL.
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PMID:The ATM gene and susceptibility to childhood T-cell acute lymphoblastic leukaemia. 982 31


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