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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Raised intracellular cyclic AMP (cAMP) has been demonstrated to exert an antiproliferative effect in myeloid cells. How the antiproliferative activity of cAMP is exerted in p210 BCR-ABL transformed myeloid cells was the subject of this investigation. It was hypothesized that cyclin dependent kinase 4, cdk4, might be a critical target enzyme to affect the related events of c-myc transcription and progression through G1 phase of the cell cycle within cells transformed by p210 BCR-ABL, and further, that cdk4 might be downregulated by cAMP to inhibit proliferation. In order to investigate the regulatory role of cdk4, synchronized cells were studied. In p210 BCR-ABL transformed cells transiting early G1 phase, treatment with a cAMP analogue led to inhibition of cyclin D1 synthesis, and marked reduction of cdk4 kinase activity. Within cells in which cdk4 was inhibited by cAMP, there was augmented interaction of E2F1 with the retinoblastoma protein, pRb in a nuclear matrix-associated cell fraction. As a result of E2F1 sequestration, raised intracellular cAMP was found to inhibit c-myc transcription in p210 BCR-ABL transformed myeloid cells synchronously transiting the early G1 phase of the cell cycle. A target of this transcriptional suppression exerted by cAMP was the E2F site of the c-myc P2 promoter. On the other hand, cyclin D1 content was not reduced by cAMP in these cells when it was applied at a later cell cycle stage at the interface between G1 and S. Corresponding to lack of cyclin D1 inhibition in these later G1-to-S phase cells, cdk4 activity was only modestly suppressed, and c-myc mRNA expression was also inhibited to a lesser degree. These studies show that Rb interaction with E2F1 is regulated by cdk4 and cyclin D1 within p210 BCR-ABL transformed leukemia cells in early G1 phase of the cell cycle. In this context, both cyclin D1 and cdk4 are subject to the level of intracellular cAMP. This interaction between Rb and E2F1, which is subject to the level of cAMP, is critical to transcriptional control of c-myc. Further, pRb regulation of E2F activity affects cellular potential for G1-S phase transition in p210 BCR-ABL transformed myeloid cells, in part, via its effect on c-myc transcription.
Leukemia 1997 Jan
PMID:Cyclic AMP negatively controls c-myc transcription and G1 cell cycle progression in p210 BCR-ABL transformed cells: inhibitory activity exerted through cyclin D1 and cdk4. 900 21

The DLX gene family is a family of divergent homeobox genes which are related to the Drosophila distal-less (Dll) gene and has been reported to be expressed primarily in the forebrain and craniofacial structures. We have previously identified a new member of this family, DLX-7. We now report that this gene is expressed in normal hematopoietic cells and leukemia cell lines with erythroid characteristics. We used an antisense oligonucleotide targeted against the translation start site of DLX-7 mRNA to inhibit its expression in a human erythroleukemia cell line K562, which expresses DLX-7 at a high level. The antisense oligonucleotide efficiently reduced the DLX-7 mRNA, while control oligonucleotides, including a mutant oligonucleotide identical to the antisense sequence except for four nucleotide mismatches, had no effect on DLX-7 mRNA level. Inhibition of DLX-7 expression decreased the plating efficiency by approximately 70% compared with control. The antisense treatment caused apoptosis, as shown by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-digoxigenin nick end labeling (TUNEL) method. Down-regulation of DLX-7 expression by antisense treatment was associated with a reduction in GATA-1 and c-myc mRNA levels. Thus, we conclude that DLX-7 is expressed in hematopoietic cells and that the inhibition of its expression results in the decreased levels of GATA-1 and c-myc genes, with an accompanying induction of apoptosis.
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PMID:Inhibition of DLX-7 homeobox gene causes decreased expression of GATA-1 and c-myc genes and apoptosis. 909 78

Vesnarinone is a positive inotropic agent used for treating congestive heart failure. We evaluated its ex vivo effects on myeloid leukemia cell lines and primary acute myelogenous leukemia cells. Vesnarinone inhibited the incorporation of radiolabeled thymidine by a myeloid cell line, HL60, in a dose-dependent manner at concentrations ranging from 0.1 to 30 microg/mL. A maximum 40% suppression was seen at a concentration of 10 microg/mL. Determination of viable cell counts by trypan blue dye exclusion method demonstrated vesnarinone to be cytocidal for HL60 cells. Vesnarinone induced DNA fragmentation as detected by electrophresis in HL60 cells after 72-hour culture; this effect was not inhibited by G-CSF. The apoptosis induced by vesnarinone was also detected by the in situ end-labeling method. Northern blot analysis showed a reduction of c-myc mRNA expression in HL60 cells by vesnarinone. However, immunostaining assay showed no change in the expression of Fas and Bcl-2 proteins. We next examined the effect of vesnarinone on primary myeloid leukemia cells derived from 10 patients: 3 cases of M1, 2 of M2, 3 of M3, 1 of M4, and 1 of M6, by the French-American-British classification. Vesnarinone inhibited the incorporation of thymidine in all cells, with a mean suppression of 58.1%. DNA electrophoresis showed induction of DNA fragmentation in cultured cells with vesnarinone for 72 hours in 8 of the 10 patients with primary leukemia. However, bone marrow mononuclear cells from healthy controls showed no growth suppression or DNA fragmentation in response to vesnarinone. These results suggest that vesnarinone may be useful in treating myeloid leukemia.
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PMID:Vesnarinone exhibits antitumor effect against myeloid leukemia cells via apoptosis. 932 55

We have evaluated the effect of two topoisomerase II (Topo II) poisons, amsacrine and doxorubicin, on the expression of the c-myc oncogene, both at the mRNA and protein levels, in the leukemia cell line, K562, and its doxorubicin-resistant counterpart, K562 DoxR. We report in this study a concentration-dependent decrease in c-myc mRNA levels upon exposure of both cell lines to amsacrine and doxorubicin, with a more pronounced effect for amsacrine in the resistant line. In either case, c-myc down-regulation closely paralleled the drug-induced growth inhibition. We have also used the technique of PCR stop-assay to detect the occurrence of DNA breaks within the P2 promoter of the c-myc gene. We have shown that Topo II-mediated breaks induced by amsacrine are probably responsible for the down-regulation of c-myc in the resistant line. In addition, amsacrine induced apoptosis only in the resistant line while doxorubicin did not induce apoptosis in any cell line. These results suggest that c-myc is not involved in the resistance of K562 DoxR cells, but can induce the apoptosis pathway in these cells, while no drug-induced apoptosis could be detected in the sensitive line.
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PMID:Transcriptional down-regulation of c-myc expression in an erythroleukemic cell line, K562, and its doxorubicin-resistant variant by two topoisomerase II inhibitors, doxorubicin and amsacrine. 962 35

Human T-cell leukemia/lymphotropic virus type I (HTLV-I) infection causes a variety of human diseases, including adult T-cell leukemia/lymphoma. The viral transactivator Tax has been implicated as a key factor in the HTLV-I-induced transformation pathway. To investigate the components of this pathway, we derived fibroblast-like cell lines, designated T6 and T9, from tail biopsies of tax-transgenic C57BL/6 mice that do not develop tumors. Phenotypic characterization of T6 and T9 cells and T6-derived subclones revealed that they differ in their abilities to form foci in vitro and tumors in vivo. The observed differences in the levels of Tax expression did not correlate with their degree of neoplastic potential. However, a control cell line derived from a nontransgenic C57BL/6 mouse did not form foci in vitro or tumors in vivo, indicating that Tax was required for the transformation process. Results of Northern analyses showed that the T9 cells and the highly malignant derivatives of T6 cells expressed elevated levels of c-myc mRNA. These findings suggest that progression of the tax-transgenic cells toward a more malignant phenotype might involve c-myc deregulation.
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PMID:Analysis of Tax-expressing cell lines generated from HTLV-I tax-transgenic mice: correlation between c-myc overexpression and neoplastic potential. 1006 80

Cyclin D1 is a weak oncogene that cooperates with c-myc activation in the development of B cell lymphomas in transgenic animals. Cyclin D1 is constantly overexpressed in human mantle cell lymphomas (MCL). However, the status of c-myc gene in these tumors is not known. We have examined the c-myc mRNA expression and genomic alterations, including mutational analysis of exon 1, intron 1, and exon 2 regulatory elements, in a series of 33 MCL, 22 typical and 11 blastoid variants. In addition, c-myc alterations were also examined in 56 nodal non-Hodgkin's lymphomas (NHL). c-myc mRNA overexpression was found in 38% (11/29) of MCL with a slightly higher frequency in blastoid variants (5/10, 50%) than in typical cases (6/19, 31%). Genetic alterations were only found in one blastoid MCL showing a three-fold c-myc gene amplification. In other nodal NHL, c-myc overexpression was found in 24% (7/29) of indolent tumors but in 70% (19/27) of aggressive variants. c-myc Genetic alterations detected in these cases were gene rearrangement and hypermutations in one Burkitt's lymphoma, and individual point mutations in intron 1 or exon 2 in 1/19 (5%) indolent and 7/16 (44%) aggressive variants. These results indicate that c-myc is overexpressed in a subset of MCL, but structural gene alterations are less frequent than in other nodal NHL.
Leukemia 1999 Dec
PMID:c-myc mRNA expression and genomic alterations in mantle cell lymphomas and other nodal non-Hodgkin's lymphomas. 1060 33

The K562 leukemia cell line is bipotential for erythroid and megakaryoblastic differentiation. The phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) activates a genetic program of gene expression in these cells leading to their differentiation into megakaryoblasts, a platelet precursor. Thus, K562 cells offer a means to examine early changes in gene expression necessary for megakaryoblastic commitment and differentiation. An essential requirement for differentiation of many hematopoietic cell types is the down-regulation of c-myc expression, because its constitutive expression blocks differentiation. TPA-induced differentiation of K562 cells causes rapid down-regulation of c-myc expression, due in part to an mRNA decay rate that is 4-fold faster compared with dividing cells. A cell-free mRNA decay system reconstitutes TPA-induced destabilization of c-myc mRNA, but it requires at least two components for reconstitution. One component fractionates to the post-ribosomal supernatant from either untreated or treated cells. This component is sensitive to cycloheximide and micrococcal nuclease. The other component is polysome-associated and is induced or activated by TPA. Although in dividing cells c-myc mRNA decays via a sequential pathway involving removal of the poly(A) tract followed by degradation of the mRNA body, TPA activates a deadenylation-independent pathway. The cell-free mRNA decay system reconstitutes this alternate decay pathway as well.
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PMID:Regulation of c-myc mRNA decay in vitro by a phorbol ester-inducible, ribosome-associated component in differentiating megakaryoblasts. 1093 49

3-Deazaadenosine (DZA), one of the potent inhibitors of S-adenosylhomocysteine hydrolase, is known to possess several biological properties including an induction of apoptosis. To evaluate a possibility that DZA may be utilized for the treatment of human leukemia, we studied molecular events of cell death induced by DZA in human leukemia HL-60 and U-937 cells. DZA induced a specific cleavage of poly ADP-ribose polymerase (PARP) and an activation of the cysteine protease caspase-3/CPP32 which is known to cleave PARP. DZA-mediated nuclear DNA-fragmentation was completely blocked in the presence of a universal inhibitor of caspases (z-VAD-fmk) or the specific inhibitor of caspase-3 (z-DEVD-fmk) unlike of cycloheximide (CHX). DNA fragmentation was preceded by the lowering of c-myc mRNA in the DZA treated cells. In addition, DZA-induced apoptosis was blocked by pretreatment with adenosine transporter inhibitors such as nitrobenzylthioinosine (NBTI) and dipyridamole (DPD). Taken together, these results demonstrate that DZA-induced apoptosis initiated through an active transport of DZA into human leukemia cells, is dependent on the caspase-3-like activity without de novo synthesis of proteins and possibly involves c-myc down-regulation.
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PMID:Induction of apoptosis in human leukemia cells by 3-deazaadenosine is mediated by caspase-3-like activity. 1119 Feb 70

To evaluate the effects of a novel 2-aminosteroid, 2-(4'-methyl-1'-piperazinyl)-3alpha-hydroxyl-5alpha-androstane-17-one (KH), on in vitro murine WEHI-3B leukemia cells, semisolid colony culture, MTT assay, morphological examination, NBT reduction, NSAE test and ACP assay were used to determine proliferation and differentiation. It was found that the growth of leukemia cells in colony and liquid cultures was inhibited by KH (10(-8)-10(-4) mol/l) after treatment for 7 days. The percentages of NBT and NSAE positive cells were 71.17 and 79.25%, respectively, after treatment with KH (10(-8)-10(-6) mol/l) for 5 days. The morphology of treated leukemia cells was identified to be macrophage-like and these cells acquired significant ACP activities. It was indicated that the ACP enzyme activities were increased as high as two and three times of the control, respectively, after treatment with 10(-8) or 10(-5) mol/l KH for 6 days. It was also indicated by DNA fragmentation in gel electrophoresis that WEHI-3B cells were induced toward apoptosis by KH (10(-8)-10(-4) mol/l) when checked at day 5. The c-myc mRNA expressions in WEHI-3B cells were decreased by 58.7% after treatment with KH (10(-8) mol/l) for 5 days. Therefore, it is first reported here that KH, a novel 2-aminosteroid, could suppress proliferation and induce differentiation of WEHI-3B leukemia cells. These differentiated cells were mature macrophage-like cells and showed characteristics of functional phagocytes acquired with acid phosphatase activity. The mechanisms underlying the above effects involved the apoptosis of WEHI-3B leukemia cells and the down-regulation of c-myc oncogene expression. It is also shown that the counts of immature granulocytes and monocytes were significantly decreased in both peripheral blood and bone marrow of BALB/c leukemia mice after KH was administrated per os for 7 consecutive days with four doses (5, 10, 15 or 20 mg/kg day), respectively. It is also observed that the enlarged spleens in leukemia mice were decreased when compared with the control.
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PMID:The effects and mechanisms of a novel 2-aminosteroid on murine WEHI-3B leukemia cells in vitro and in vivo. 1133 17

We describe a patient with myelodysplastic syndrome (MDS) that transformed to Burkitt's acute lymphoblastic leukaemia (ALL). The leukaemic blasts were negative for peroxidase staining, and expressed CD10, CD19, CD22, CD38, human leucocyte antigen (HLA)-DR and surface immunoglobulin (sIg) M, but neither sIgD nor sIgG were expressed. Chromosomal study during the ALL phase showed t(8;22)(q24;q11) in addition to the karyotypes determined during the MDS phase. Furthermore, overexpression of c-myc mRNA was confirmed in ALL blasts. These findings indicate that MDS transformed to Burkitt's ALL through multiple cytogenetic evolutions, the final event of which seems to be overexpression of the c-myc gene.
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PMID:Burkitt's acute lymphoblastic leukaemia transformation after myelodysplastic syndrome. 1172 13


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