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)

Chronic myeloid leukaemia (CML) is characterized cytogenetically by a t(9;22)(q34;ql1) reciprocal translocation which gives origin to a hybrid BCR-ABL gene, encoding a p2lO(BCR-ABL) fusion protein with elevated tyrosine kinase activity and transforming abilities. The t(9;22) was suggested to be associated with genomic imprinting of centromeric regions of chromosomes 9 and 22, but the genes directly affected by the translocation, ABL and BCR, were shown not to be imprinted. For most diagnostic and research purposes the BCR-ABL gene can be efficiently identified by reverse-transcription and polymerase chain reaction (RT/PCR) amplification of its fusion transcripts, which can be quantified by competitive PCR and similar assays for assessment of residual disease in the follow-up of therapy. In the great majority of CML patients the BCR-ABL transcripts exhibit a b2a2 and/or a b3a2 junction; in rare cases, the only detectable BCR-ABL transcripts have unusual junctions, such as b2a3, b3a3, e1a2 or e6a2. There is a recent suggestion that the BCR-ABL gene may not be always 'functional', since extremely low levels of BCR-ABL transcripts can be found in leucocytes from normal individuals and, conversely, it appears that no BCR-ABL transcription can be detected in a proportion of Ph-positive haematopoietic progenitors from some CML patients. The role, if any, of the reciprocal ABL-BCR hybrid gene in CML is unknown. Although its mRNA message is in frame, no ABL-BCR fusion protein has yet been identified in CML patients. The blast crisis of CML has been variably associated with abnormalities of proto-oncogenes, such as RAS and MYC, or of tumour suppressor genes, in particular RB, p53 and p16, or with the generation of chimeric transcription factors, as in the AML1-EVI1 gene fusion. It is likely, therefore, that multiple and alternative molecular defects, as opposed to a single universal mechanism, underlie the acute transformation of the disease.
Leukemia 1996 May
PMID:The molecular biology of chronic myeloid leukaemia. 865 67

Evidence that the D13S25 locus lies close to a potential tumour suppressor gene implicated in the pathogenesis of B-CLL has been based on detection of LOH and bi-allelic loss using the pH2-42 probe. The SspI polymorphism detected by this probe has been identified by sequencing adjacent clones and a polymorphic (TA)n repeat has been found. Amplification of the region encompassing both polymorphic markers by PCR increases the informativity to 80%.
Leukemia 1996 Nov
PMID:PCR analysis of polymorphisms at the D13S25 locus. 889 72

Sezary cell leukaemia (SCL) is a mature T-cell leukaemia with characteristic cerebriform nuclei, whereas Sezary syndrome (SS) involves a mature T-cell lymphoma with a similar nuclear morphology. We have examined these diseases by cytogenetics chromosome painting and fluorescence in situ hybridization (FISH). Both diseases had complex cytogenetic abnormalities. All three cases of SCL investigated had inv(14)(q11:q32) and two had iso(8q). No case of SS had these abnormalities but, instead, iso(17q) or 17p+ was present in the three cases of SS investigated and FISH indicated loss of heterozygosity due to deletion of a region at 17p 13 that included the tumour suppressor gene P53, implicating it in this malignancy. One case of SCL had iso(17q). The abnormalities of chromosomes 8 and 14 in SCL are commonly observed in T-prolymphocytic leukaemia (T-PLL) and suggest that SCL may be a variant of T-PLL rather than of SS.
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PMID:Relationship of T leukaemias with cerebriform nuclei to T-prolymphocytic leukaemia: a cytogenetic analysis with in situ hybridization. 907 12

ADAMs (A disintegrin and metalloproteinase) are a recently discovered family of proteins with significant primary sequence similarity to the reprolysin family of snake venomases. These ADAMs closest known homologues are the type III reprolysin enzymes which have been demonstrated to be, among other things potent type IV collagenases. ADAMs are putative membrane linked proteins with several domains including a metalloproteinase domain, a potential integrin binding domain, a cysteine rich sequence and an EGF like sequence. They have been implicated in a wide variety of functions including basement membrane degradation and cell-cell and cell-matrix interactions. We have used RT-PCR and Northern blotting to characterise the expression of members of this family in cells derived from a variety of haematological malignancies including leukaemia (HL60 and Jurkat), erythroleukaemia (K562), lymphoma (U937 and Cupillo) and myeloma (U266B1). We find clear expression of four members of this novel family of proteins but note differences in the expression levels of each member. The ADAMs known as MADM (ADAM10), MCMP (ADAM12, MDC9) and Metargidin (ADAM15) which all possess potentially active metalloproteinase domains are expressed in all these cell types to significant levels. The putative tumour suppressor gene MDC (ADAM11) is expressed at very low levels in all cells examined. As ADAMs may have both potential metalloproteinase activity and adhesive domains we wish to explore the role of these proteins with regard to pathophysiology of haematological malignancy such as egression of leukaemic cells from the bone marrow.
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PMID:Expression of members of the novel membrane linked metalloproteinase family ADAM in cells derived from a range of haematological malignancies. 919 13

Many human tumours show perturbations of a pathway that includes the D-cyclins, their associated cyclin-dependent kinases, and specific kinase inhibitors. The focal point of this pathway is the product of the retinoblastoma tumour suppressor gene, pRb, which imposes a block on G1 phase progression. Thus, the major role of the cyclin D-dependent kinases is to overcome this block by initiating the phosphorylation of pRb. Excessive activity of this pathway is likely to lead to excessive cell proliferation. Conversely, accumulation of the inhibitors is associated with the cessation of cell division.
Leukemia 1997 Apr
PMID:Regulation and function of the cyclin-dependent kinase inhibitor p16CDKN2. 920 87

Ataxia-telangiectasia (A-T) is a recessive multi-system disorder caused by mutations in the ATM gene at 11q22-q23 (ref. 3). The risk of cancer, especially lymphoid neoplasias, is substantially elevated in A-T patients and has long been associated with chromosomal instability. By analysing tumour DNA from patients with sporadic T-cell prolymphocytic leukaemia (T-PLL), a rare clonal malignancy with similarities to a mature T-cell leukaemia seen in A-T, we demonstrate a high frequency of ATM mutations in T-PLL. In marked contrast to the ATM mutation pattern in A-T, the most frequent nucleotide changes in this leukaemia were missense mutations. These clustered in the region corresponding to the kinase domain, which is highly conserved in ATM-related proteins in mouse, yeast and Drosophila. The resulting amino-acid substitutions are predicted to interfere with ATP binding or substrate recognition. Two of seventeen mutated T-PLL samples had a previously reported A-T allele. In contrast, no mutations were detected in the p53 gene, suggesting that this tumour suppressor is not frequently altered in this leukaemia. Occasional missense mutations in ATM were also found in tumour DNA from patients with B-cell non-Hodgkin's lymphomas (B-NHL) and a B-NHL cell line. The evidence of a significant proportion of loss-of-function mutations and a complete absence of the normal copy of ATM in the majority of mutated tumours establishes somatic inactivation of this gene in the pathogenesis of sporadic T-PLL and suggests that ATM acts as a tumour suppressor. As constitutional DNA was not available, a putative hereditary predisposition to T-PLL will require further investigation.
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PMID:Clustering of missense mutations in the ataxia-telangiectasia gene in a sporadic T-cell leukaemia. 928 6

Cytogenetic deletions of the short arm of chromosome 12 are common recurring alterations found in a wide range of haematological neoplasias, including childhood acute lymphoblastic leukaemia (ALL), the most frequent paediatric malignancy. Such a loss of genetic material suggests the presence of a tumour suppressor gene which plays an important role in growth regulation or in the differentiation of haemopoietic stem cells. To substantiate this hypothesis and to determine more precisely the chromosomal location of this putative gene, we applied a deletion mapping strategy based on the detection of loss of heterozygosity (LOH) at specific genomic loci in tumour cells. 13 polymorphic markers were used to screen DNA samples from 20 children with ALL. LOHs at 12p12.3 were observed in almost 50% of informative B-cell precursor ALL patients analysed. This is one of the most frequent genetic alterations found in this disease. A common region of LOH was delimited by the markers D12S89 (distal) and D12S358 (proximal), separated by a genetic interval of approximately 3 cM. We refined the position of the putative 12p tumour suppressor gene to a physical interval of <1.3 Mb, a crucial step towards the identification of candidate genes. A yeast artificial chromosome clone contig that spans the entire critically deleted region includes two known genes: TEL, a member of the ets family of transcription factors, and p27KIP1, a cyclin-dependent kinase inhibitor.
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PMID:Frequent deletion of chromosome 12p12.3 in children with acute lymphoblastic leukaemia. 935 10

Chronic lymphoid leukaemias are clonal expansions of B and T cells with mature membrane phenotype. Cytogenetic study of these cases usually requires mitogenic stimulation and can often be hindered by a lack of response of the tumour cells to mitogen, poor quality metaphases, complex markers and proliferation of normal cells. In situ hybridisation with fluorescence-labelled chromosome-specific centromeric DNA probe, single or low copy sequences and whole chromosome paints which hybridise to complementary sequences allow the detection of numerical and structural abnormalities on metaphase and interphase cells with much greater efficiency. Comparative genomic hybridisation uses whole genomic tumour DNA as probe which is hybridised to normal metaphases. It is particularly useful for detecting chromosomal changes without being dependent on the dividing tumour cells. The application of these techniques to the investigation of chronic lymphoid leukaemias is reviewed with emphasis on the work done in our laboratory on trisomy 12 and the tumour suppressor region 13q14 in chronic lymphocytic leukaemia, translocation t(11;14) (q13;q32) in mantle cell lymphoma and other chronic B cell leukaemias, inv(14) (q11q32), i(8q) and complex markers in T prolymphocytic leukaemia.
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PMID:The impact of molecular cytogenetics on chronic lymphoid leukaemia. 940 94

Research on the genetic basis of CLL is progressing at a rapid pace. The development of new techniques such as FISH, comparative genomic hybridisation (CGH) and a whole range of molecular methods is being applied to identify abnormalities in this relatively common B-cell leukaemia. The abnormalities may be of a different nature. There are some which are clearly associated with particular forms of the disease and usually with aggressive characteristics. The best examples are deletions at 11q23 seen in younger patients with generalised lymphadenopathy and inferior prognosis; trisomy 12, commonly associated with an increased proportion of prolymphocytes (CLL/PL) and more progressive disease; 17p abnormalities, chiefly mutations and deletions of p53, although rare, seem to be associated with transformation such as Richter syndrome, with CLL/PL and poor response to therapy. Abnormalities at 13q, though not correlated with particular clinical syndromes, are the subject of intense interest due to the possibility that one or more tumour suppressor genes relevant to the pathogenesis of CLL may be identified. Two areas in which work is being focused are 13q14 and 13q12. Finally, the incidence of familial cases of CLL, which has been known for a number of years, will lead to an international effort to collect familial cases, which ultimately will allow a genetic linkage study to discover a CLL "susceptibility gene". The presentations at the IWCLL were up-to-date, stimulating and pointed the way forward to further rapid progress in this exciting field.
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PMID:The search for genetic clues in chronic lymphocytic leukemia. 947 Oct 56

T-prolymphocytic leukaemia (T-PLL) is a rare, sporadic leukaemia similar to a mature T-cell leukaemia seen in some patients with Ataxia Telangiectasia (A-T), a recessive multisystem disorder caused by mutations of the ATM gene at chromosome 11q23. ATM sequence mutations have been reported in 46% of T-PLL cases, but some cases also have karyotypic abnormalities at 11q, including 11q23. This led us to investigate the structure of the ATM locus in a panel of eight cases, two of which had 11q23 abnormalities. As expected, nucleotide changes were detected in some samples. Two remission samples were wild type. To test for structural lesions, DNA fibres were hybridized with a contig of four labelled cosmids spanning the ATM locus. In all samples there were structural lesions and in four samples both alleles were affected. This provides strong evidence for our suggestion that ATM acts as a tumour suppressor during T-PLL tumorigenesis. Some additional role for ATM during T-PLL tumorigenesis is possible since nucleotide changes were present in addition to structural lesions disrupting both alleles. The mechanism of inactivation appeared to be unusual because multiple structural lesions on one allele were often observed.
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PMID:ATM is usually rearranged in T-cell prolymphocytic leukaemia. 948 43


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