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)

Mutations of the p53 tumour suppressor gene occur in 20% of chronic myeloid leukaemia (CML) patients in blastic crisis, but it is still uncertain whether this inactivation plays a role in the pathogenesis of blastic transformation or in maintaining the leukaemic proliferation in CML, as it does in several solid tumours. We have previously shown that more than 50% of both normal and CML CD34+ cells express the p53 protein. However, haemopoietic cells at different phases of the cell cycle express p53 with different conformations, suggesting that the function of p53 may be closely regulated during the cell cycle. In order to elucidate the mechanism by which p53 suppresses cell proliferation, we evaluated the effects of inhibiting p53 expression on cell cycle and cell kinetics of chronic phase CML (n = 12) and normal (n = 7) bone marrow light-density cells and purified CD34+ progenitors by using an 18-mer modified antisense oligonucleotide which targets the region covering the six base pairs immediately before the first codon and the first four coding codons of p53. We found that the number of cells positive for the cell cycle-specific nuclear antigen Ki67 and for the BrdU monoclonal antibody (McAb) was significantly increased after p53 antisense olignucleotide treatment. At the same time, p53 protein expression was completely abrogated in both light-density and CD34+ cells. In addition, DNA analysis by flow cytometry demonstrated that the number of cells in quiescent phases of the cell cycle (G0-G1) was significantly decreased after exposure of light-density cells to p53 antisense oligomers, whereas the number of cells in S or G2-M phases was increased. Furthermore, the longer the incubation time the higher the increase in cell proliferation. Treatment of CML, cells with p53 antisense oligomers also resulted in significantly increased numbers of CFU-GM colonies. Our data suggest that p53 is a negative regulator of cell proliferation and its action is mediated through changes in cell cycle kinetics, mainly before the S phase. We can further speculate that the loss of p53 function, at the time of blastic crisis of CML, may play a role, in combination with other genetic changes (p210 BCR/ABL, Rb gene abnormality, others to be defined), in inducing disturbances in cell proliferation, differentiation, and apoptosis.
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PMID:Modulation of cell kinetics and cell cycle status by treating CD34+ chronic myeloid leukaemia cells with p53 antisense phosphorothioate oligonucleotides. 778

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

Chronic myeloid leukaemia (CML) is a malignant clonal disorder of the haematopoietic stem cell. Treatment of CML patients with interferon alpha (IFN-alpha) has induced haematological and cytogenetic remission. Interferons transcriptionally activate target genes through the JAK-STAT and interferon regulated factors (IRFs) family pathways. Interferon regulated factor-1 (IRF-1) is a transcriptional activator of genes critical for cell growth, differentiation and apoptosis. The skipping of exons 2 or 2 and 3 of IRF-1 in patients with myelodysplastic syndromes and acute myelogenous leukaemia suggests that this factor may have a critical role in leukaemogenesis. The role of IRF-1 in CML is currently unknown. Therefore, mutational analysis of IRF-1 was performed and its expression pattern was also studied in CML patients. We studied IRF-1 in peripheral blood mononuclear cells of 21 patients in chronic phase CML. No point mutations were identified at the cDNA level. Surprisingly, fourfold reduction of full-length IRF-1 mRNA expression was established in 17/21 patients compared with normal individuals. Low expression of full-length IRF-1 was observed in conjunction with high levels of aberrantly spliced mRNAs, reported for the first time. In three patients who were also analysed during blastic transformation, further reduction of full-length IRF-1 mRNA was observed. These findings demonstrate that, in CML patients, IRF-1 can produce high levels of aberrant spliced mRNAs with subsequent reduction in the levels of full-length IRF-1 mRNA. This observation is consistent with the notion that exon skipping may constitute another mechanism of tumour suppressor gene inactivation in this disease.
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PMID:Low expression of interferon regulatory factor-1 and identification of novel exons skipping in patients with chronic myeloid leukaemia. 1235 2

The deregulated kinase activity of p210-BCR/ABL oncoproteins, hallmark of chronic myelogenous leukaemia (CML), induces and sustains the leukaemic phenotype, and contributes to disease progression. Imatinib mesylate, a BCR/ABL kinase inhibitor, is effective in most of chronic phase CML patients. However, a significant percentage of CML patients develop resistance to imatinib and/or still progresses to blast crisis, a disease stage that is often refractory to imatinib therapy. Furthermore, there is compelling evidence indicating that the CML leukaemia stem cell is also resistant to imatinib. Thus, there is still a need for new drugs that, if combined with imatinib, will decrease the rate of relapse, fully overcome imatinib resistance and prevent blastic transformation of CML. We recently reported that the activity of the tumour suppressor protein phosphatase 2A (PP2A) is markedly inhibited in blast crisis CML patient cells and that molecular or pharmacologic re-activation of PP2A phosphatase led to growth suppression, enhanced apoptosis, impaired clonogenic potential and decreased in vivo leukaemogenesis of imatinib-sensitive and -resistant (T315I included) CML-BC patient cells and/or BCR/ABL+ myeloid progenitor cell lines. Thus, the combination of PP2A phosphatase-activating and BCR/ABL kinase-inhibiting drugs may represent a powerful therapeutic strategy for blast crisis CML patients.
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PMID:ReSETting PP2A tumour suppressor activity in blast crisis and imatinib-resistant chronic myelogenous leukaemia. 1695 42