Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The in vitro action of recombinant human leukemia inhibitory factor (LIF) and 1-beta-D arabinofuranosylcytosine (ara-C) was studied on the human leukemia cell line U 937. Parameters investigated included monitoring of transcript levels of the proto-oncogenes C-MYC, C-FOS, and C-FMS, and analysis of nitroblue tetrazolium (NBT) reduction and of surface expression of the C3 bi receptor. Furthermore clonal proliferation of U 937 cells was assessed in soft agar cultures. The results indicate that both agents have only little effects on U 937 cells when acting alone. When combined in culture, however, they synergize to induce monocytic differentiation of U 937 cells as disclosed by significant increase of cells capable of reducing NBT and displaying surface C3 bi receptor that was accompanied by reduction of clonogenicity in colony assays. Induction of differentiation and inhibition of proliferation of U 937 cells was preceded by downregulation of transcript levels of C-MYC, increase of C-FOS mRNA, and induction of accumulation of C-FMS mRNA. By sequential use of LIF and ara-C we also demonstrate that the basis of synergism of both agents does not involve mechanisms at the level of receptor ligation but that synergism may be initiated by complementary intracellular metabolic cascades.
Leukemia 1990 Sep
PMID:Synergistic effect of recombinant human leukemia inhibitory factor (LIF) and 1-beta-D-arabinofuranosylcytosine (Ara-C) on proto-oncogene expression and induction of differentiation in human U 937 cells. 214 31

The BCL2 (B cell lymphoma/leukemia-2) and C-HA-RAS oncogenes encode membrane-associated proteins of 26 and 21 kilodaltons, respectively. Although RAS proteins have long been known for their ability to bind and hydrolyze GTP, recent investigations suggest that BCL2 encodes a novel GTP-binding protein (S. Haldar, C. Beatty, Y. Tsujimoto, and C. M. Croce, Nature [London] 342:195-198, 1989). Cotransfection of BCL2 and HA-RAS oncogenes resulted in morphological transformation of early-passage rodent fibroblasts, rendering these cells tumorigenic in animals and enabling them to grow in semisolid medium. In contrast, cotransfection of BCL2 with oncogenes that encode nuclear proteins (E1A and C-MYC) did not produce malignant transformation, whereas HA-RAS did complement with these genes. These findings suggest that proteins encoded by oncogenes such as BCL2 and HA-RAS, although having similar subcellular locations and perhaps similar biochemical properties, can regulate distinct complementary pathways involved in cellular transformation.
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PMID:Complementation by BCL2 and C-HA-RAS oncogenes in malignant transformation of rat embryo fibroblasts. 219 51

The expression of the myeloperoxidase (MPO) gene was studied, by means of Northern blot analysis in 14 cases of acute myeloid leukemia (AML), 11 cases of chronic myeloid leukemia (CML), and 6 cases of CML blast crisis, and in HL60 cells before and after induction of terminal differentiation with retinoic acid (RA), phorbol esters (TPA), or vitamin D. The expression of a panel of cell cycle-related genes, namely C-MYC, histone H3, ornithine decarboxylase, P53, vimentin, and calcyclin, was also studied in the same cell populations. Our results indicate that: (a) MPO gene expression (steady state mRNA levels) is strictly confined to the first stages of myeloid differentiation, reaching its peak at the promyelocyte stage and becoming undetectable in mature granulocytes and monocytes; (b) cells devoid of any detectable MPO enzymatic activity such as leukemic basophils have a high content of MPO mRNA; and (c) MPO gene expression is not related to the growth activity of the cell population. Finally, our results show that the pattern of expression of growth-regulated genes in the neoplastic myeloid disorders AML, CML, and CML blast crisis is remarkably different.
Leukemia 1989 Jun
PMID:Expression of the myeloperoxidase gene in acute and chronic myeloid leukemias: relationship to the expression of cell cycle-related genes. 254

The BCL2 (B cell lymphoma/leukemia -2) and C-MYC oncogenes become activated by chromosomal translocations involving the immunoglobulin heavy chain locus in human follicular lymphomas and Burkitt lymphomas, respectively. Though much is known about the biological actions of C-MYC, little information is available concerning the functions of BCL2, particularly in human B cells. Using a gene transfer approach we contrasted the effects of deregulated BCL2 and C-MYC expression in a human EBV-immortalized B cell line GM607B. Both BCL2 and C-MYC enhanced the ability of GM607B cells to grow in reduced serum and in limiting dilution cultures. These findings provide direct evidence that BCL2 can alter the growth characteristics of human B lymphocytes, thus strengthening arguments for its role in the pathogenesis of human lymphomas.
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PMID:Deregulated BCL2 expression enhances growth of a human B cell line. 278 59

Moloney murine leukemia virus (MoMuLV) is a retrovirus which lacks an oncogene. It is, however, highly oncogenic in rats and mice, in whom it induces thymic lymphomas. These lymphomas are clonal tumors and appear four to six months following virus inoculation. Although provirus integration is random in virus infected non-tumor cells, it shows regional specificity in these tumors, thus suggesting that insertional mutagenesis may play an important role in tumor induction and progression. Our studies have revealed four common DNA regions for provirus insertion in these tumors (Mlvi-1, Mlvi-2, Mlvi-3 and c-Myc), while studies from other laboratories have revealed two additional ones (pvt-1/mis-1 and pim-1). Mlvi-1, Mlvi-2 and Mlvi-3 represent three independent logi since there is no homology between them molecular clones that identify them and they map on different rat chromosomes. It is interesting however that two of them (Mlvi-1 and Mlvi-2), as well as pvt-1/mis-1, map to mouse chromosome 15 which is known to become trisomic in murine thymic lymphomas. In addition to the specificity of provirus integration, tumor induction is also associated with amplification of the proviral DNA. This amplification may be favored during oncogenesis because cells that carry insertion mutations in multiple oncogenes may exhibit growth advantage over cells in which only single insertion mutations have occurred. This could happen because the effect of these mutations may be additive or because there is a synergistic relationship between multiple loci during oncogenesis. This was indeed suggested by the appearance of concerted provirus insertions in Mlvi-1 and Mlvi-2. Alternatively, the amplification of the provirus during tumor induction may be selected because it provides for elevated levels of viral gene products that participate in the process of oncogenesis. Such products may be coded by sequences in the gag/pol region. We indeed present evidence here for a 2 kb tumor specific gag/pol transcript which is expressed in these thymomas. Our analysis of Mlvi-1 and Mlvi-2 has revealed the following. Mlvi-1 contains at least one open reading frame which is conserved among species and which preliminary evidence indicates may be expressed in the thymomas. Additionally Mlvi-1 appears to be present in more than one copy per haploid genome in both rats and humans. In Mlvi-2 we have shown the presence of a transcribed region downstream from the cluster of the integrated proviruses in the MoMuLV induced thymic lymphomas. However this transcript is expressed mostly in rat embryo fibroblasts.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Oncogenesis by Moloney murine leukemia virus. 359 29

The human T-cell leukemia virus type I oncoprotein Tax transcriptionally deregulates a wide variety of viral and cellular genes. Tax deregulation of gene expression is mediated through interaction with a variety of structurally unrelated cellular transcription factors, as Tax does not bind DNA in a sequence-specific manner. Although most of these cellular transcription factors have been shown to mediate activation by Tax, we have recently demonstrated that members of the basic helix-loop-helix (bHLH) family of transcription factors, which play a critical role in progression through the cell cycle, mediate repression by Tax. In this report, we examined whether Tax might repress transcription of the tumor suppressor p53, as the p53 gene has recently been demonstrated to be regulated by the bHLH protein c-Myc. Furthermore, loss or inactivation of the p53 gene has been shown to be causally associated with oncogenic transformation. We show that Tax represses transcription of the p53 gene and that this repression is dependent upon the bHLH recognition element in the p53 promoter. Together, these results suggest that Tax may promote malignant transformation through repression of p53 transcription.
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PMID:Transcriptional repression of p53 by human T-cell leukemia virus type I Tax protein. 749 59

Glucocorticoids inhibit the expression of critical cell cycle-regulatory genes. The G1 cyclin gene CcnD3, which encodes cyclin D3, is inhibited by dexamethasone in P1798 murine T lymphoma cells. Glucocorticoids also inhibit expression of the catalytic partner of cyclin D3, Cdk4. Inhibition of these two genes results in a decrease in the ability to phosphorylate the Rb-1 tumor suppressor gene product. Stable transformation with SV40 T antigen expression vectors prevents glucocorticoid-mediated cell cycle arrest, which is consistent with the conclusion that glucocorticoids inhibit Rb-1 phosphorylation. Overexpression of cyclin D3 suffices to restore Rb-kinase activity in glucocorticoid-treated cells. Nevertheless, overexpression of cyclin D3 does not prevent glucocorticoid inhibition of cell proliferation. Cells transformed with Cdk4 expression vectors, with or without cyclin D3 expression vectors, also undergo G0 arrest in the presence of dexamethasone. Glucocorticoids inhibit c-Myc expression in lymphoid cells, and transient expression of c-Myc protein attenuates the lytic response in glucocorticoid-treated human leukemia cells (R. Thulasi, D. V. Harbour, and E. B. Thompson, J. Biol. Chem., 268: 18306-16312, 1993). However, P1798 cells stably transfected with c-Myc expression vectors are sensitive to glucocorticoid-mediated G0 arrest. Such transformants withdraw from the cell cycle when treated with dexamethasone. P1798 cells were transformed so as to express both c-Myc protein and cyclin D3 in the presence of glucocorticoids. These Myc/D3 cells continue to proliferate in the presence of dexamethasone, and virtually all of these cells are capable of entering S phase in the presence of the steroid. Rapid apoptotic cell death occurs when wild-type P1798 cells are treated with dexamethasone in serum-free medium. Myc-transformed and cyclin D3-transformed cells also die rapidly when treated with glucocorticoids in the absence of serum. T antigen transformants are resistant to glucocorticoid-mediated apoptosis in serum-free medium. Double transformants that express both cyclin D3 and c-Myc are also resistant to apoptosis in the presence of dexamethasone. We conclude that inhibition of both CcnD3 and c-Myc genes is critical to glucocorticoid-mediated G0 arrest. Furthermore, those genes that convey resistance to growth arrest also convey resistance to cell death.
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PMID:c-Myc and cyclin D3 (CcnD3) genes are independent targets for glucocorticoid inhibition of lymphoid cell proliferation. 766 96

Incubation of CCRF CEM C7A human lymphoblastic leukaemia cells with etoposide (VP16) or N-methylformamide (NMF) induced apoptotic cell death. The kinetics of onset of apoptosis was determined and compared with that for dexamethasone-treated cells. The drugs induced 50% apoptosis at different rates: etoposide by approximately 18 h, NMF by 40 h and dexamethasone (DEX) by 52 h. In each case, the onset of apoptosis above 10% was preceded by a delay period. This was 8 h for etoposide, between 8 and 12 h for NMF and 36 h for dexamethasone. When cells were incubated for 36 h with dexamethasone and the drug washed out, addition of NMF induced apoptosis without any delay, suggesting that certain common biochemical events are required to prime the cells for apoptosis. However, cells treated for 8 h with NMF did not undergo immediate apoptosis on the addition of DEX. Analysis of the cellular content of the c-myc protein showed this to be undetectable by 2, 6 and 12 h after treatment with etoposide, NMF and DEX respectively. The rapid onset of NMF-induced cell death after a 36 h DEX pretreatment occurred 24 h after the loss of expression of c-Myc protein, suggesting that the expression of c-myc is not required for drug-induced cell death. In contrast to DEX-induced apoptosis, concomitant incubation of cells with NMF or etoposide and 200 nM of the protein synthesis inhibitor cycloheximide did not inhibit apoptotic cell death. The idea that drugs with different modes of action initiate conserved responses which engage a programmed cell death is discussed.
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PMID:Induction of apoptosis by anti-cancer drugs with disparate modes of action: kinetics of cell death and changes in c-myc expression. 773 16

Suppression of c-myc expression is observed during induced differentiation of several myeloid cell lines and it has been attributed to the cell growth arrest that accompanies terminal differentiation. To dissect the role of c-Myc in the proliferation-differentiation switch we have studied c-myc expression in K562 cells exposed to several chemical agents. This model system allowed us to discriminate between the growth arrest and differentiation phenomena as well as the induction of differentiation along two different lineages (erythroid and myelomonocytic). Our results showed that c-myc expression did not significantly decrease when growth inhibition is reversible, either by treatment with a differentiating agent such as hydroxyurea (which induced erythroid differentiation) or by a non-differentiating agent such as interferon-alpha. In contrast, c-myc expression decreased when cells underwent terminal differentiation, either along the myelomonocytic (by 12-O-tetradecanoylphorbol-13-acetate) or erythroid (by 1-beta-D-arabinofuranosylcytosine) lineages. These results indicated that c-myc down-regulation is not obligatory for growth arrest and non-terminal differentiation of human myeloid cells. In contrast, c-myc down-regulation occurred in terminal differentiation, but induction of myelomonocytic differentiation resulted in a greater loss of c-myc mRNA than induction of erythroid differentiation.
Leukemia 1993 Nov
PMID:Down-regulation of c-myc gene is not obligatory for growth inhibition and differentiation of human myeloid leukemia cells. 823 Dec 50

The v-abl oncogene of Abelson murine leukemia virus encodes a deregulated form of the cellular nonreceptor tyrosine kinase. v-Abl activates c-myc transcription, and c-Myc is an essential downstream component in the v-Abl transformation program. To explore the mechanism by which v-Abl activates c-myc transcription, a cotransfection assay was developed. We show that transactivation of a c-myc promoter by v-Abl requires the SH1 (tyrosine kinase) and SH2 domains of v-Abl; the C-terminal domains are not required for transactivation. The assay also identified the E2F site in the c-myc promoter as a v-Abl-responsive element. In addition, multimerized E2F sites were shown to be sufficient to confer v-Abl-dependent activation on a minimal promoter. This is the first identification of a v-Abl response element for transcriptional activation. v-Abl tyrosine kinase-dependent changes in proteins binding the c-myc E2F site were also demonstrated, including induction of a complex containing DP1, p107, cyclin A, and cdk2. Identification of v-Abl-dependent changes in E2F-binding proteins provides an important link between v-Abl, transcription, cell cycle regulation, and control of cellular growth.
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PMID:v-Abl activates c-myc transcription through the E2F site. 852 18


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