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)

The BCR/ABL oncogene in chronic myelogenous leukemia produces an activated tyrosine kinase fusion protein (p210). Like other tyrosine kinase oncogenes, BCR/ABL can abrogate the interleukin-3 (IL-3) dependence of lymphoid cell lines. To investigate the ability of BCR/ABL to generate growth factor independence in myeloid cells, the IL-3 dependent myeloid cell line NFS/N1.H7 (H7) was transfected with the p210BCR/ABL-containing plasmid, pGD210. Stable clones A54 and A74 were capable of IL-3 independent growth and tumor formation in syngeneic mice. Relief of growth factor dependence was not mediated by autocrine release of IL-3. The baseline proliferation rate of the BCR/ABL transformed cells was greater than that of the parental H7 cells maximally stimulated by IL-3. Abundant constitutive expression of c-myc, c-jun, and c-fos was observed in the p210BCR/ABL transfectants even in low serum conditions. In contrast, c-myc expression in H7 cells was dependent upon IL-3 stimulation, and neither c-jun nor c-fos was highly expressed following IL-3 stimulation in H7 cells. Thus, BCR/ABL transformation and relief of IL-3 dependence involve not only pathways that can substitute for IL-3 induced growth via tyrosine kinase mediated signals, but also pathways that recruit constitutive c-jun and c-fos expression.
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PMID:BCR/ABL confers growth factor independence upon a murine myeloid cell line. 137 13

DNA methylation plays an important role in gene regulation. We have analyzed the methylation status of CCGG sites in and around the human proto-oncogene c-myc in blood cells from patients with acute and chronic leukemias and with myelodysplastic syndromes using restriction endonucleases. The 5' region of c-myc was unequivocally hypomethylated in all the 58 specimens studied, including 10 from normal bone marrow and 1 from human placenta. In contrast, the 3' region was hypermethylated in a great majority of cases. However, this region was hypomethylated in 1 of 12 patients with de novo acute myeloid leukemia, 1 of 6 patients with chronic myeloid leukemia, and 4 of 5 patients with acute myeloid leukemia preceded by a documented stage of myelodysplastic syndromes. One possible mechanism for the 3' region of c-myc to have remained hypomethylated may be a "delayed methylation" during transforming events toward a more aggressive stage of the disease, but the precise mechanism is unknown.
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PMID:Methylation status of c-myc oncogene in leukemic cells: hypomethylation in acute leukemia derived from myelodysplastic syndromes. 146 40

The effects of various compounds which modulated the intracellular signal transduction on the induction of class I major histocompatibility complex (MHC) antigens by recombinant human interferon-gamma (rIFN-gamma) were investigated using K562, chronic myelogenous leukemia cells. Class I or class II MHC antigens were not expressed in untreated K562 cells and rIFN-gamma (600 units/ml) weakly induced class I antigens on the cells. Among the compounds tested, verapamil but not the calcium ionophore A23187 enhanced the rIFN-gamma-induced class I antigen expression at both the surface molecule and mRNA levels and enhancement by verapamil occurred in a dose-dependent manner at non-toxic concentrations examined (approximately 50 microM). Verapamil alone had no inducible effect on MHC antigen expression. Deprivation of Ca2+ in culture medium by ethylene glycol-bis(beta-aminoethyl ether) N,N,N',N'-tetraacetic acid (EGTA) could not cause an enhancement of class I antigen induction by rIFN-gamma. Simultaneous exposure of K562 cells to rIFN-gamma (600 units/ml) and recombinant human tumor necrosis factor (rTNF; 1000 units/ml) in combination with verapamil (50 microM) resulted in a further increase of class I antigens in the cells. The expressions of c-myc oncogene in K562 cells were not changed when the cells were treated with rIFN-gamma (600 units/ml) or verapamil (50 microM), either alone or in combination. These results indicate that verapamil synergistically interacts with rIFN-gamma on the class I antigen induction in K562 cells irrespective of c-myc gene expression and that class I antigen induction in this cell line may not be relevant to calcium influx triggered by IFN-gamma.
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PMID:Effect of verapamil on the class I major histocompatibility complex antigen expression in K562 chronic myelogenous leukemia cells treated with recombinant human interferon-gamma. 151 24

The increased activity in cancer cells of inosine 5'-monophosphate dehydrogenase (IMP DH, EC 1.1.1.205), the rate-limiting enzyme of de novo GTP biosynthesis, was suggested as a sensitive target for chemotherapy. Tiazofurin (NSC 286193), through its conversion to the active metabolite, thiazole-4-carboxamide adenine dinucleotide (TAD), is a strong inhibitor of IMP DH. In our clinical trial, tiazofurin caused return to the chronic phase in patients with chronic granulocytic leukemia in blast crisis (Tricot, G.; Jayaram, H.N.; Weber, G.; Hoffman, R. Tiazofurin: Biological effects and clinical uses. Int. J. Cell Cloning 8:161-170; 1990). In K562 human leukemic cells, tiazofurin down-regulated the expression of c-Ki-ras and c-myc oncogenes, which was followed by induced differentiation. We now report down-regulation by tiazofurin of the c-Ki-ras oncogene in a patient with chronic granulocytic leukemia in blast crisis. A single tiazofurin infusion (2,200 mg/m2) on days one and two decreased IMP dehydrogenase activity (the apparent t1/2 was 30 min), GTP concentration (the apparent t1/2 was 6 hr), and expression of ras (the apparent t1/2 was 8 hr) and c-myc (the apparent t1/2 was 38.5 hr) oncogenes in the leukemic cells. No further tiazofurin was given, because on days three and four the chemotherapeutic impact became evident in a tumor-lysis syndrome and the blast cells were cleared from the periphery by day five. The decrease in IMP DH activity, GTP concentration, and expression of c-Ki-ras oncogene were early markers of the successful chemotherapeutic impact of tiazofurin in a patient with chronic granulocytic leukemia in blast crisis.
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PMID:Tiazofurin down-regulates expression of c-Ki-ras oncogene in a leukemic patient. 170 12

Diagnosis- and/or prognosis-related alterations of (proto) oncogenes may be detected in neuroblastoma (N-myc), carcinoma of breast and ovary (HER2/neu), NHL (c-myc, bcl-2), CML (c-abl/bcr), and some other neoplasias. A wide variety of methods for the detection of gene alterations can be applied. The methods of detection have to be chosen according to the expected mechanisms of oncogene activation, the availability of adequately prepared tissue, and the technical standard of the laboratory. The sensitivity, specificity, and quantitation of morphological techniques (immunohistochemistry and in situ hybridization) is restricted and their results have to be interpreted most carefully. Whenever possible, at least two different techniques should be used, preferably on two different levels, i.e. RNA/DNA and protein. Furthermore, the combination of morphological and non morphological methods should be aspired.
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PMID:[Oncogenes and oncogene products--possibilities and significance of their detection]. 170 8

Cancer is caused by specific DNA damage. Several common mechanisms that cause DNA damage result in specific malignant disorders: First, proto-oncogenes can be activated by translocations. For example, translocation of the c-myc proto-oncogene from chromosome 8 to one of the immunoglobulin loci on chromosomes 2, 14, or 22 results in Burkitt's lymphomas. Translocation of the c-abl proto-oncogene from chromosome 9 to the BCR gene located on chromosome 22 produces a hybrid BCR/ABL protein resulting in chronic myelogenous leukemia. Second, proto-oncogenes can be activated by point mutations. For example, point mutations of genes coding for guanosine triphosphate-binding proteins, such as H-, K-, or N-ras or G proteins, can be oncogenic as noted in a large variety of malignant neoplasms. Proteins from these mutated genes are constitutively active rather than being faithful second messengers of periodic extracellular signals. Third, mutations that inactivate a gene can result in tumors if the product of the gene normally constrains cellular proliferation. Functional loss of these "tumor suppressor genes" is found in many tumors such as colon and lung cancers. The diagnosis, classification, and treatment of cancers will be greatly enhanced by understanding their abnormalities at the molecular level.
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PMID:Molecular mechanisms of cancer. 181 12

The effects of 1 alpha, 25-dihydroxyvitamin D3 (VD3) on proliferation, differentiation, and macromolecular synthesis in the new Philadelphia chromosome-positive chronic myelogenous leukemia cell line, RWLeu-4, were investigated. Binding of [3H]VD3 was saturable, with approximately 2000-3000 sites/cell, and half-maximal binding occurring at 0.21-0.33 nM. Treatment of RWLeu-4 cells with VD3 induced 24R-hydroxylase activity, a marker of vitamin D3 responsiveness in many tissues. Exposure of RWLeu-4 cells to VD3 also inhibited proliferation and DNA synthesis with a 50% effective dose of 3.5-10 nM within 72 h; in addition, protein and RNA synthesis were inhibited by VD3 treatment. Exposure of RWLeu-4 cells to 5 nM VD3 for 72 h caused 50% of the cells to differentiate into macrophage/monocyte type cells as judged by nitroblue tetrazolium staining and adherence to plastic. Progressive expression of cell surface maturation-specific antigens of the monocyte/macrophage lineage was induced by treatment of RWLeu-4 cells with VD3 for 24 to 72 h at doses that inhibited cellular proliferation. c-myc RNA, which is constitutively expressed in RWLeu-4 cells, increased after 0.5 h of treatment with 50 nM VD3 and then rapidly decreased to barely detectable levels after 4 h of treatment. Finally, the in vitro tyrosine kinase activity associated with the p210bcr-abl oncogene product was decreased approximately 50% by VD3 treatment. Because of the presence of a functional receptor-effector system for VD3 and multiple biological responses to the hormone, these cells provide a unique model system with which to probe the specific effects of VD3 on cell growth and differentiation in chronic myelogenous leukemia.
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PMID:Effects of 1 alpha, 25-dihydroxyvitamin D3 on the human chronic myelogenous leukemia cell line RWLeu-4. 215 72

The relative abundances of c-myc-related RNA in the total cellular RNA of peripheral blood leukocytes from 36 patients with leukaemia have been compared with those in normal peripheral blood leukocytes and in HL60 cells. Varying amounts of c-myc-related RNA were found in RNAs from leukocytes from patients with ANLL, CGL and ALL. High concentrations (comparable with that in HL60 cells) were found in 13 (36%) of the leukaemias and lower, but still significant, concentrations in a further 15 (42%). Low concentrations of c-myc-related RNA, comparable to that in normal leukocytes, were found in 2 of 8 CGLs, 1 of 12 ANLLs, and 5 of 5 CLLs. DNAs from 11 leukaemia patients' leukocytes, in which c-myc-related RNA concentrations ranged from very high to very low, were examined for rearrangements and/or amplification of the c-myc gene. No rearrangements were detected, and the small degree of amplification (2- to 4-fold at most) found was not correlated with increased levels of c-myc RNA. There was, however, a noteworthy (though incomplete) correlation between elevated levels of c-myc-related RNA and the occurrence of higher proportions of blast cells in leukocyte populations from leukaemic patients. It is suggested that high levels of c-myc-related RNA in a population of peripheral blood leukocytes indicate the presence of a high proportion of leukaemic leukocytes that are maturation-arrested at early stages of development.
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PMID:Expression of the myc gene locus in populations of leukocytes from leukaemia patients and normal individuals. 242 11

Comparisons of the level of proto-oncogene expression in neoplastic cells and in normal cells are being made to determine the role of these genes in neoplastic development. Recent papers have reported that leukemic cells differ from normal cells in having higher c-myc RNA levels. One problem in interpreting these data is that leukemic and normal cell populations differ in the proportion of immature cells present in each. The studies described here, using chronic phase chronic myelogenous leukemia (CML) cells, compared the level of proto-oncogene expression in immature and mature myeloid cells. Substantial differences in the level and pattern of expression were found with the immature cells containing higher c-myc RNA levels and the mature cells containing higher histone H3 RNA levels. c-fos RNA levels parallel the distribution of monocytes. While the c-myc RNA level in the CML cell population as a whole is similar to that in normal marrow cell populations and less than that in the bone marrow cells of patients with acute myelogenous leukemia (AML), c-myc RNA levels in subpopulations of immature chronic phase CML myeloid cells approximate that found in AML cells. Additionally, the studies described here suggest that the presence of high c-myc and c-fos RNA levels in light density immature cells may be a unique characteristic of acute myeloid leukemic cells.
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PMID:Differing patterns of proto-oncogene expression in immature and mature myeloid cells. 244 85

Proto-oncogenes were studied by Southern blotting in 12 patients with chronic myelogenous leukemia in blast crisis (CML). Cytogenetically, all cases had Philadelphia (Ph1) chromosome and 4 had additional chromosomal abnormalities including +8, +19, i(17q), double Ph1. The bcr gene was rearranged in all cases and the region of breakage points were located in the 5.8 kb Bgl II-Bam HI fragment of bcr. In a case with double Ph1 the breakage points of bcr were thought to be different from each other. We analyzed other proto-oncogenes (N-ras, H-ras, c-myc and myb) by Southern blotting, but did not find any abnormalities.
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PMID:Southern blot analysis of Bcr, N-ras, H-ras, c-myc and myb proto-oncogenes in blast crisis of chronic myelogenous leukemia. 274 49


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