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)

Myelodysplastic syndrome (MDS) is a common neoplasm of haematopoietic pluripotent stem cells. Although one third of MDS patients evolve to acute myeloid leukaemia (AML), little is understood about the mechanisms responsible for this progression. We have previously detected the frequent loss of heterozygosity (LOH) on the short arm of chromosome 1 in blast crisis of chronic myelocytic leukaemia. In this study, we examined the chromosomal arm 1p for allelic loss in the progression of MDS to AML, using 17 microsatellite markers spanning chromosome 1 in 20 patients who progressed from MDS to AML. DNA was extracted from slides of bone marrow smears. In each patient, DNA from MDS was analysed alongside DNA from AML. Allelic loss on 1p was observed in six of the 20 individuals (30%). Serial cytogenetic information was available in five of the six patients with LOH on 1p; no deletions in this region were detected. Three samples showed LOH at all informative loci on 1p. The other three samples showed LOH on at least one but not all loci on 1p with consensus regions of LOH located distal to D1S253 (1p36.3) and probably proximal to D1S496 (1p32-). Our results suggest that tumour suppressor genes that play an important role in the progression of MDS to AML may reside in at least two different regions on 1p.
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PMID:Progression of myelodysplastic syndrome: allelic loss on chromosomal arm 1p. 1284 90

Two proteins, p16INK4A and p14ARF, originating from the same gene locus CDKN2A, use different promoters and alternative reading frames. p16INK4A is translated from alpha transcript and p14ARF is from beta transcript. These two proteins, which are inactivated in some human malignancies, are possible tumour suppressor candidates. In this study, we investigated the expression of p16INK4A and p14ARF mRNAs in haematological malignancies. We studied eight normal bone marrow samples, three reactive granulocytic hyperplasia patients, and 21 haematological malignancy patients, including seven acute myelogenous leukaemia, four acute lymphoblastic leukaemia, five myelodysplastic syndrome, five chronic myelogenous leukaemia (CML). p16INK4A and p14ARF mRNA expression was assayed by reverse transcriptase polymerase chain reaction. Normal bone marrows and reactive granulocytic hyperplasia showed barely detectable expression of either mRNA. In contrast, p16INK4A and p14ARF mRNA expression was abnormally increased in patients with haematological malignancies. Especially in CML, overexpression of p16INK4A and p14ARF mRNAs was more frequent than in controls (80 and 60%, respectively, P < 0.05). In conclusion, p16INK4A and p14ARF mRNA expression was frequently increased in haematological malignancies, especially in CML. We suggest that overexpression of these mRNAs may be related to the pathogenesis of haematological malignancies.
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PMID:Overexpression of p16INK4A and p14ARF in haematological malignancies. 1527 71

Normal cell development and function is dependent upon controlled gene expression. DNA methylation is an epigenetic modification that can play an important role in the control of gene expression. DNA methylation at cytosine residues in gene promoter CpG sequences is known to inhibit gene transcription. Inappropriate inhibition of the transcription of tumour suppressor genes, genes that inhibit angiogenesis and metastasis and genes involved in DNA repair by uncontrolled methylation, can lead to unregulated growth and proliferation of a cell and carcinogenesis. Promoter hypermethylation affecting the p16 gene, resulting in gene silencing, has been shown to occur in many human solid tumours and a 'hypermethylation profile' in some leukaemias has been defined. The molecular mechanisms by which aberrant DNA methylation takes place during carcinogenesis are still not clear. However, the large number of target genes (involved in tumorigenesis) that are silenced by aberrant methylation suggests that inhibition of this process may have potential as cancer therapy. Decitabine (NSC-127716, Dacogen; SuperGen) is a potent and specific hypomethylating agent and an inhibitor of the DNA methyltransferase activity that mediates DNA methylation. Decitabine has been shown to have a broad range of antineoplastic activity in preclinical studies. This agent has exhibited significant activity in the treatment of patients with myelodysplastic syndrome, chronic myeloid leukaemia and acute myeloid leukaemia, although clinical Phase I and II studies with solid tumours have not been very promising. Phase II and III studies are currently ongoing to evaluate decitabine, both alone and in combination, in various stages of these haematological malignancies.
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PMID:DNA methylation in haematological malignancies: the role of decitabine. 1464 Sep 42

The putative tumour suppressor gene gravin is down-regulated in several solid tumours and is implicated in tumorigenesis. We have evaluated the expression levels of the gravin gene in the CD34(+)/blast cells of a range of myeloid malignancies as compared with controls using real-time quantitative polymerase chain reaction (PCR). Gravin was markedly down-regulated in 41 of 41 patients with acute myeloid leukaemia (AML), nine of 10 patients with myelodysplastic syndromes (MDS) and 33 of 33 patients with chronic myeloid leukaemia (CML), of whom 24 were in blast crisis (BC). We have shown that gravin is consistently down-regulated in the CD34(+)/blast cells of myeloid malignancies and may play a role in the molecular pathogenesis of these disorders.
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PMID:Low expression of the putative tumour suppressor gene gravin in chronic myeloid leukaemia, myelodysplastic syndromes and acute myeloid leukaemia. 1528 43

Myelodysplastic syndrome (MDS), an acquired clonal disorder of haemopoietic progenitor cells, is characterized by haemopoietic insufficiency associated with cytopenias, leading to serious morbidity plus the additional risk of leukaemic transformation. In MDS an acquired insult to the haemopoietic stem cell leads to impaired differentiation and myelodysplasia. However, there is increasing evidence that the marrow failure of MDS is immune-mediated. A model of MDS pathophysiology suggests that transformation of normal stem cells induces an autoimmune T-cell response with the bone marrow as the target organ. This autoimmune attack results in chronic overproduction of pro-apoptotic cytokines, especially tumour necrosis factor alpha (TNFalpha). In addition, several reports have revealed that approximately 10% of MDS patients have clinical autoimmune disorders. This review illustrates the cellular/molecular mechanisms and the implication of the tumour suppressor gene interferon regulatory factor-1 (IRF-1) in the pathophysiology of MDS-associated autoimmune deregulation.
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PMID:Myelodysplasia-associated autoimmunity: clinical and pathophysiologic concepts. 1547 94

Transcriptional silencing of tumour suppressor genes (TSG) due to hypermethylation is a common event in human tumours. The three members of the KIP/CIP family of cyclin dependent kinase inhibitors (CDKIs), p21(CIP 1), p27(KIP 1), and p 57(KIP 2), play key roles in cell cycle regulation, but little is known about their methylation in myeloid neoplasia. Therefore, we analysed 9 haematopoietic cell lines, 67 myelodysplastic syndrome (MDS) and 26 acute myeloid leukaemia (AML) cases as well as 11 controls. p 57(KIP 2) hypermethylation was found in 4/9 cell lines, but methylation of p21(CIP 1) and p27(KIP 1) was infrequent. All patient samples analysed were methylation-negative for these three genes.
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PMID:Absence of p21(CIP 1), p27(KIP 1) and p 57(KIP 2) methylation in MDS and AML. 1593 16

Transcriptional silencing because of hypermethylation is now recognised to be a hallmark of human tumours. In contrast to acute myeloid leukaemia (AML), comparably little is known about aberrant methylation in myelodysplastic syndrome (MDS), a heterogeneous clonal stem cell disorder with a risk of transformation into secondary AML of up to 30%. Recent evidence demonstrates that suppressor of cytokine signalling SOCS-1, a negative regulator of cytokine pathways, may act as a tumour suppressor gene, and inactivation because of hypermethylation was shown in various malignancies. Employing a newly developed quantitative real-time polymerase chain reaction-based methylation assay we analysed, for the first time, SOCS-1 methylation in MDS and found disease-specific hypermethylation in 27 of 86 MDS patients (31%). Demethylation experiments provided direct evidence that aberrant methylation of SOCS-1 induces transcriptional silencing in myeloid cells. In addition, by analysing the expression of signal transducers and activators of transcription (STAT)-induced genes we provide for the first time evidence that the activity of the Janus kinase/STAT pathway is increased in primary patient samples showing SOCS-1 hypermethylation.
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PMID:Hypermethylation of the suppressor of cytokine signalling-1 (SOCS-1) in myelodysplastic syndrome. 1602 49

We report the isolation of the 5' flanking region of GRAF (GTPase regulator associated with the focal adhesion kinase), previously described as a putative tumour suppressor gene of acute myelogenous leukaemia and myelodysplastic syndrome, and demonstrate its promoter activity in reporter gene assays. Two putative protein-binding sites are identified of which one was sensitive to CpG methylation. The suppressed GRAF expression could be restored in leukaemia cell lines by treatment with a demethylating agent and an inhibitor of histone deacetylases. In contrast to normal tissues, which tested negative for GRAF promoter methylation, 11 of 29 (38%) bone marrow samples from patients with acute myeloid leukaemia or myelodysplastic syndrome were positive.
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PMID:Characterisation of the GRAF gene promoter and its methylation in patients with acute myeloid leukaemia and myelodysplastic syndrome. 1640 24

Decitabine is a hypomethylating agent. Its action in DNA leads to the reactivation of tumour suppressor genes and the subsequent differentiation of cancer cells. In a randomised, phase III trial in patients (n = 170) with myelodysplastic syndromes (MDS), intravenous decitabine (45 mg/m(2)/day for 3 consecutive days every 6 weeks) combined with supportive care achieved a higher response rate (including eight complete and seven partial responses) than supportive care alone, which achieved no responses (17% vs 0%; p < 0.001). The median times to response and duration of response were 3.3 and 10.3 months in the phase III trial. In three phase II studies in patients (n = 29-87) with MDS treated with decitabine (40 or 50 mg/m(2)/day for 3 days every 5-6 weeks), the percentage of patients achieving a complete or partial response or an improvement ranged from 26% to 49%, and the median duration of response or improvement ranged from 4.9 to 8.3 months. The main adverse event associated with decitabine is myelosuppression.
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PMID:Decitabine: in myelodysplastic syndromes. 1674 15

The suppressor of cytokine signalling-1 (SOCS1) protein is a tumour suppressor. Hypermethylation of SOCS1 gene, resulting in transcriptional silencing, is suggested to play an important role in cancer development. We sought to characterise SOCS1 methylation in primary myelodysplastic syndrome (MDS) and clarify its clinical implications. The methylation status of SOCS1 was analysed by methylation-specific polymerase chain reaction in 114 patients with primary MDS and serial studies were performed in 29 of them. SOCS1 methylation occurred in 54 patients (47.4%), and was more frequent in patients with high-risk MDS than in those with low-risk (52.6% vs. 25.8%, P = 0.011). SOCS1 methylation was closely associated with NRAS mutation (P = 0.010) and inversely associated with good-risk karyotype (P = 0.021). With a median follow-up of 17 months (range: 1-231 months), two patients acquired SOCS1 methylation during disease progression. In two patients, SOCS1 methylation present at diagnosis, disappeared after haematopoietic stem cell transplantation. Patients with SOCS1 methylation had a higher cumulative risk of leukaemic transformation than those without (55.8% vs. 27.7% at 3 years, P = 0.004). This difference remained significant within the subgroup of patients with high-risk MDS (67.3% vs. 45.1% at 3 years, P = 0.045). This is the first report to demonstrate the clinical relevance of SOCS1 methylation in MDS. It may play an important role in the pathogenesis of MDS, especially among patients with high-risk subtypes.
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PMID:Clinical implications of SOCS1 methylation in myelodysplastic syndrome. 1697 23


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