Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

BCR-ABL is a chimeric oncogene generated by translocation of sequences from the c-abl protein-tyrosine kinase gene on chromosome 9 into the BCR gene on chromosome 22. Alternative chimeric proteins, p210BCR-ABL and p190BCR-ABL, are produced that are characteristic of chronic myelogenous leukemia and acute lymphoblastic leukemia, respectively. Their role in the etiology of human leukemia remains to be defined. Transformed murine hematopoietic cells can be used as a model of BCR-ABL function since these cells can be made growth factor independent and tumorigenic by the action of the BCR-ABL oncogene. We show that the BCR-ABL oncogenes prevent apoptotic death in these cells by inducing a Bcl-2 expression pathway. Furthermore, BCR-ABL-expressing cells revert to factor dependence and nontumorigenicity after Bcl-2 expression is suppressed. These results help to explain the ability of BCR-ABL oncogenes to synergize with c-myc in cell transformation.
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PMID:Tumorigenic activity of the BCR-ABL oncogenes is mediated by BCL2. 777 99

Eosinophil leukaemia is a rare and poorly defined entity characterized by neoplastic proliferation of eosinophil cell line. This form of the hypereosinophilic state is considered to be a variant form of CML, although as a diseases entity is not generally accepted. A history of a patients is reported, whose clinical course is thought to fulfill the requirements of eosinophil leukaemia. On the basis of the initial results (pathological lymphogram, eosinophilia, Ph-negativity) lymphogranulomatosis was suspected and explorative laparotomy was performed. However, only marked eosinophilic infiltration of the spleen was detected. After splenectomy his disease was stable without treatment for six months when his leukocytosis and eosinophilia increased. Despite the administration of hydroxyurea the leukocyte count exceeded 100 x 10(9)/l (eosinophil cells 70%), and the bone marrow revealed massive (80%) eosinophilic infiltration. Neither Ph-chromosome, nor cabl and bcr gen rearrangement were demonstrated, but the expression and amplification of c-myc oncogene indicated disease progression. Interferon therapy produced long-term clinical and haematological improvement, but blastic transformation was developed in the second year of his disease. Autopsy showed multiple organ involvement characteristic of CML, but no marked eosinophilic infiltration was found. The feature of this case suggest that eosinophil leukaemia might represent an uncommon form of Ph-negative CML.
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PMID:[Eosinophilic leukemia: a rare form of Philadelphia chromosome negative chronic myeloid leukemia?]. 805 96

Many haematologic malignancies carry characteristic chromosomal translocations, which are thought to play an important role in the pathogenesis of these tumours. The t(8; 14) translocation in Burkitt's lymphoma was one of the first characterized at the molecular level. In this translocation the c-myc oncogene at chromosome 8q24 becomes deregulated by enhancer elements of the immunoglobulin heavy chain locus at chromosome 14q32 leading to a very aggressive B cell malignancy. Translocations involving an overexpressed c-myc gene are also found in AIDS-associated lymphoma or in T cell leukaemias, or they develop during tumour progression of a low grade B cell malignancy into a high grade B cell tumour in an additional cytogenetic change. A different mechanism of oncogene activation in a leukaemia specific chromosomal abnormality is found for CML, where c-abl sequences are fused into the bcr locus, or in the t(4; 11) of acute childhood leukaemia involving the recently identified ALL-1 gene at chromosome 11q23 resulting in a malfunctioning, structurally altered oncogene. Thus, in the past molecular and somatic cell genetic studies have clarified many details in aetiology and progression of leukaemias and lymphomas which are useful for applications in clinical diagnostics, and which in the future will be helpful in designing a therapy based on a molecular understanding.
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PMID:Chromosomal translocations in leukaemia. 814 18

Overexpression of the proto-oncogenes c-erbB-2, c-myc, and c-ras have been associated with neoplastic transformation in a variety of tumours. We investigated expression of these oncogenes in 5 canine melanoma cell lines and 6 clonal derivatives of 1 of the cell lines, CML-6M, to determine what impact overexpression had on tumour cell growth and metastatic potential. All 11 cell lines were tumourigenic at subcutaneous inoculation sites in nude mice, but spontaneous metastasis to lung was a characteristic of only the CML-6M cell line and 3 of 6 clonal derivatives of CML-6M. Investigation of oncogene overexpression revealed no obvious pattern of expression among the 5 tumour-derived cell lines whereas overexpression of c-erbB-2 and c-myc was consistently found in the 3 clonal cell lines characterized by high metastatic potential, and in primary and metastatic mouse xenografts induced by these lines. This data suggests involvement of overexpression of these genes in development of canine melanoma and associates their overexpression with metastatic potential in nude mice.
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PMID:Overexpression of c-erbB-2 and c-myc but not c-ras, in canine melanoma cell lines, is associated with metastatic potential in nude mice. 823 7

The BCR-ABL gene plays a central role in the pathogenesis of chronic myelogenous leukemia. Despite a detailed understanding of the regions of BCR and ABL required for transformation by BCR-ABL, little is known about the signalling pathway by which BCR-ABL causes transformation. The nuclear oncogene c-myc plays a critical role in BCR-ABL transformation. Levels of c-myc RNA are high in cells transformed by BCR-ABL, and overexpression of dominant negative forms of myc blocks transformation by BCR-ABL. These findings suggest that myc may be a useful therapeutic target in BCR-ABL-related leukemias.
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PMID:The role of myc in transformation by BCR-ABL. 825 15

The "constitutive" expression of the c-myc gene was detected in leukemia cells obtained from 4 patients with an acute myeloid leukemia, 3 with chronic myeloid leukemia and 1 with a myelodysplastic syndrome. Studies were undertaken to determine whether or not the myc gene was rearranged or mutated in exon I within a 3'Pvu II region, a transcriptional attenuation site. Studies to explore the possibility of a point mutation in the N-ras gene were also conducted. No abnormalities were detected in either gene. Studies should be undertaken evaluating the possibility of a post-transcriptional mechanism, such as alteration of RNA stability, which could be responsible for the constitutive expression of c-myc gene.
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PMID:Analysis of the c-myc and N-ras genes in acute myelogenous leukemia cells which manifest the constitutive expression of the c-myc gene. 831 7

Uniformly modified oligonucleotide N3'-->P5' phosphoramidates, where every 3'-oxygen is replaced by a 3'-amino group, were synthesized. These compounds have very high affinity to single-stranded RNAs and thus have potential utility as antisense agents. As was shown in this study, the oligonucleotide phosphoramidates are resistant to digestion with snake venom phosphodiesterase, to nuclease activity in a HeLa cell nuclear extract, or to nuclease activity in 50% human plasma, where no significant hydrolysis was observed after 8 h. These compounds were used in various in vitro cellular systems as antisense compounds addressed to different targeted regions of c-myb, c-myc and bcr-abl mRNAs. C-myb antisense phosphoramidates at 5 microM caused sequence and dose-dependent inhibition of HL-60 cell proliferation and a 75% reduction in c-myb protein and RNA levels, as determined by Western blot and RT-PCR analysis. Analogous results were observed for anti-c-myc phosphoramidates, where a complete cytostatic effect for HL-60 cells was observed at 1 microM concentration for fully complementary, but not for mismatched compounds, which were indistinguishable from untreated controls. This was correlated with a 93% reduction in c-myc protein level. Moreover, colony formation by the primary CML cells was also inhibited 75-95% and up to 99% by anti-c-myc and anti-bcr-abl phosphoramidate oligonucleotides, respectively, in a sequence- and dose-dependent manner within a 0.5 nM-5 microM dose range. At these concentrations the colony-forming ability of normal bone marrow cells was not affected. The presented in vitro data indicate that oligonucleotide N3'-->P5' phosphoramidates could be used as specific and efficient antisense agents.
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PMID:Oligonucleotide N3'-->P5' phosphoramidates as antisense agents. 862 85

The proliferation of chronic myelogenous leukemia (CML) cells and the transformation of normal hematopoietic cells by BCR-ABL appear to require the expression of a functional MYC protein, suggesting an approach to treatment of Philadelphia leukemias based on simultaneous targeting of BCR-ABL and c-MYC. To test this hypothesis, CML-blast crisis (CML-BC) primary cells were treated in vitro with bcr-abl and c-myc antisense phosphorothioate oligodeoxynucleotides ([S]ODNs), individually or in combination. Compared with antisense ODNs targeting of individual oncogenes, downregulation of both BCR-ABL and c-MYC by specific antisense [S]ODNs resulted in a synergistic antiproliferative effect. Colony formation of normal bone marrow cells was not affected by either treatment. To assess the therapeutic potential of multiple oncogene downregulation, SCID mice injected with CML-BC primary cells were treated systematically with equal doses of bcr-abl or c-myc antisense [S]ODNs or with a combination of both antisense [S]ODNs. Compared with mice treated with individual compounds, the disease process was significantly retarded in the group treated with both [S]ODNs as revealed by flow cytometry, clonogenic assay, and RT-PCR analysis to detect leukemic cells in mouse tissue cell suspensions. These effects correlated with a markedly increased survival of leukemic mice treated with both antisense [S]ODNs. Leukemic cells harvested from antisense [S]ODN-treated mice were sensitive to the effects of antisense [S]ODNs in vitro, suggesting that the treatment can be successfully repeated. These data demonstrate the therapeutic potential of targeting multiple cooperating oncogenes.
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PMID:Antisense oligodeoxynucleotide combination therapy of primary chronic myelogenous leukemia blast crisis in SCID mice. 870 8

Differentiation inhibitory factor (nm23 protein) inhibited the induction of differentiation of mouse myeloid leukemia M1 and WEHI-3BD+ and human erythroleukemia HEL, KU812, and K562 cells. Block of differentiation may be associated with the aggressive behavior of leukemia. To examine the role of nm23 in human myeloid leukemia, we investigated the relative levels of nm23-H1, nm23-H2, and c-myc transcripts in 42 patients with acute myelogenous leukemia (AML), and in 5 with chronic myelogenous leukemia at chronic phase by reverse transcriptase polymerase chain reaction. The expression of nm23-H1 and -H2 but not of c-myc in AML was significantly higher than that in normal blood cells. Among AMLs, acute monocytic leukemia (presentation with AML-M5 morphology) was especially associated with elevated nm23-H1 and -H2 mRNA levels. On the other hand, the elevated levels of c-myc expression in AML-M5 were less evident. An analysis of correlation between nm23 expression and clinicopathological parameters showed that resistance to initial chemotherapy is associated with increased nm23-H1 mRNA levels and that a high initial white blood cell count is associated with increased nm23-H2 mRNA levels. Elevated nm23-H1 mRNA levels were associated with significantly reduced the overall survival of AML, especially of AML-M5 patients. The present results indicate that nm23-H1 and -H2 are overexpressed in AML and especially nm23-H1 gene expression predicts the prognosis of AML, especially of AML-M5.
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PMID:Differentiation inhibitory factor nm23 as a new prognostic factor in acute monocytic leukemia. 889 23

Chronic myelogenous leukemia (CML) has a progressive course but little is known about the biologic characteristics of disease progression. This study was designed to assess the changes in cell proliferative characteristics, apoptosis, the expression of the bcl-2 and c-myc genes between the time of initial diagnosis and entrance into the blastic phase of the disease. We observed that the rate of cell proliferation decreased and the cell death rate did not significantly change as the disease accelerated. The level of bcl-2 expression was significantly higher in accelerated/blastic phase cells than in the chronic phase cells in the population as a whole, however, the bcl-2 expression level did not change in blast cell subpopulation. c-myc Expression was significantly higher in the blast cell subpopulation of accelerated/blastic phase than in that of earlier phases of the disease. In conclusion, the characteristics of CML cells, namely proliferation rate, c-myc and bcl-2 change during the course of the disease. It is possible that the change in c-myc expression plays a causative role in evolution of the blastic phase from the chronic phase.
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PMID:Bcl-2 and c-myc expression, cell cycle kinetics and apoptosis during the progression of chronic myelogenous leukemia from diagnosis to blastic phase. 927 59


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