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

Steel factor (SF) synergizes with a variety of hemopoietins to support the growth and differentiation of human progenitor cells. The human factor-dependent cell line MO7 has been used as a model to study the interaction of SF with other growth factors such as GM-CSF, because both factors support the proliferation of this cell line and are synergistic in combination. Previous studies have shown that this effect is not readily explained by the synergistic activation of early, cytosolic signal transduction intermediates such as tyrosine kinases, Raf-1, MAP2 kinase, or phospholipase C gamma. In an attempt to further explore the biological and biochemical mechanisms of the synergy between SF and GM-CSF, we examined the effects of these growth factors on the regulation of nuclear proto-oncogenes, cell cycle control genes, and G1-->S transition of MO7 cells. Individually, GM-CSF was a much more potent growth factor for MO7 cells than SF, particularly under serum-free conditions. Only GM-CSF, but not SF, was able to stimulate G1-->S transition of MO7 cells after factor deprivation for 24 h. Northern blot analyses showed also differential effects of GM-CSF and SF on the expression of some nuclear proto-oncogenes and G1 cyclins. GM-CSF (10 ng/ml), but not SF (20 ng/ml) increased the expression of c-myc and cyclin D2 mRNA, whereas both factors caused transient increases of c-fos and cyclin D3 mRNAs. When added simultaneously, GM-CSF and SF induced an at least additive increase of c-fos mRNA expression; this effect required the presence of fetal calf serum. No additive effects of GM-CSF and SF on c-myc, cyclin D2 or D3 mRNA expression were observed. C-jun and c-myb mRNAs were constitutively expressed in the MO7 cell line, but not further increased after stimulation with GM-CSF or SF for 15 min to 48 h. The inability of SF to induce growth promoting genes such as c-myc and cyclin D2 may explain why this cytokine does not support sustained proliferation of MO7 cells. These observations suggest that SF and GM-CSF exert different effects on the expression of genes involved in regulatory pathways of cell proliferation, but the molecular mechanism of synergy remains to be elucidated.
Leukemia 1994 May
PMID:Signal transduction of steel factor and granulocyte-macrophage colony-stimulating factor: differential regulation of transcription factor and G1 cyclin gene expression, and of proliferation in the human factor-dependent cell line MO7. 751 43

Cyclins are regulatory subunits of the cyclin dependent kinases (CDKs), the enzymes that drive the cell through the respective phases and check-points of the cell cycle. The expression of cyclins in non-tumor cells, regulated by timely induction of their synthesis and proteolysis, is scheduled, occurring at discrete periods of the cell cycle. Using multiparameter flow cytometry we have recently observed that expression of cyclins B1 and E in individual normal lymphocytes mitogenically stimulated by phytohemagglutinin (PHA) and lymphocytic leukemic MOLT-4 cells was similar, restricted to particular phases of the cycle: cyclin B1 was detected only in G2+M- and cyclin E in late G1 and early S-phase cells. In the present study we have measured the expression of cyclins A, D2 and D3 in these cells. The presence of cyclin A was restricted to late S and G2 phases, both in the case of lymphocytes and of MOLT-4 cells. Over 95% of the non-stimulated lymphocytes were both cyclin D2 and D3 negative. Mitogenic stimulation with PHA-induced expression of cyclins D2 and D3 in over 50% cells, which corresponds to the percentage of cells that respond to this mitogen in cultures. Expression of these proteins peaked between 8 and 24 h after addition of PHA, and then decreased at the time of cell entrance to S. During exponential growth (48-72 h after stimulation with PHA) expression of the D-type cyclins was diminished: only between 5-10% of the lymphocytes had levels of cyclin D3 as high as G1 cells between 8-24 h after PHA stimulation. Populations of proliferating lymphocytes and MOLT-4 cells were very heterogeneous in terms of expression of D-type cyclins by individual cells. While expression of cyclin D2 in exponentially growing MOLT-4 cells was similar to that of proliferating lymphocytes, the percent of cells expressing cyclin D3 as well as the degree of expression, was higher in MOLT-4 cells, regardless of the phase of the cycle. These results, with our earlier observations of the untimely expression of cyclins B1 and E in several other tumor lines, suggest that altered expression of cyclins may be a frequent feature of malignancy.
Leukemia 1995 May
PMID:Expression of cyclins A, D2 and D3 in individual normal mitogen stimulated lymphocytes and in MOLT-4 leukemic cells analyzed by multiparameter flow cytometry. 776 53

The cyclin D1 gene can be transcriptionally activated in lymphoid tumours as a result of chromosomal rearrangements but is normally silent in B and T lymphocytes. By isolating cyclin D1-related cDNAs from a B-lymphoid cell line, we identified clones that contain the coding sequences of human cyclin D2. The predicted 289 amino acid protein shares 63% identity with human cyclin D1. Although cyclin D2 transcripts were detected in many lymphoid cell lines, it was not ubiquitously expressed and there was no apparent correlation with cyclin D1 levels. For example, two B-cell leukaemia lines, JVM-2 and Karpas 620, both of which have 11q13 translocations and express cyclin D1, contained markedly different amounts of cyclin D2. An obvious distinction between these cells is that the JVM-2 line, which expresses high levels of cyclin D2, was immortalized by Epstein-Barr virus (EBV). We subsequently found that cyclin D2 is consistently expressed in group III Burkitt's lymphoma (BL) and in lymphoblastoid cell lines immortalized by EBV, but not in group I BLs, in which expression of the EBV genome is more restricted. The data imply that the D-type cyclins may have non-overlapping functions at specific stages of lymphocyte differentiation and that the expression of cyclin D2 may be influenced, directly or indirectly, by EBV.
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PMID:Cyclins D1 and D2 are differentially expressed in human B-lymphoid cell lines. 845 31

To understand how the growth of T-cells transformed by Human T-cell leukemia virus type I (HTLV-I) is deregulated, we analysed the expression of cell-cycle regulatory genes in HTLV-I infected and non-infected T-cell lines. We investigated the gene for 6 cyclins, 4 cyclin-dependent kinases, and 5 cyclin-dependent kinase inhibitors, and found the following: (1) HTLV-I infected T-cell lines preferentially expressed cyclin D2, whereas cyclin D3 was the major D-type cyclin in HTLV-I negative T-cell lines; (2) HTLV-I infected T-cell lines expressed strikingly low levels of p18Ink4 compared with those that were HTLV-I negative; (3) HTLV-I infected T-cell lines expressed high levels of p21Waf1/Cip1/Sdi1, whereas p21Waf1/Cip1/Sdi1 was undetectable in HTLV-I negative T-cell lines. These features were also found in T-cells immortalized by Tax1, which we established. Therefore, it is strongly suggested that Tax1 alters the expression of these cell-cycle regulatory genes.
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PMID:Expression of cell-cycle regulatory genes in HTLV-I infected T-cell lines: possible involvement of Tax1 in the altered expression of cyclin D2, p18Ink4 and p21Waf1/Cip1/Sdi1. 862 84

The level of various G1 cyclins and cyclin-dependent kinases (cdks) present in the nuclei of synchronized ML-1 human myeloblastic leukemia cells was determined as a function of time after initiation of cell growth with insulin-like growth factor-1 (IGF-1) and transferrin (Tf), and following induction of differentiation with transforming growth factor-beta1 (TGF-beta1). Cyclin E and cdk2 were expressed at relatively high levels in the nuclei of proliferation-stimulated cells, whereas cyclin D1 and cdk5 were expressed at comparably high levels in the nuclei of differentiation-induced cells. In the nuclear extracts from proliferation-stimulated cells, cyclin E complexed specifically with cdk2, whereas in nuclear extracts from differentiation-induced cells, cyclin D1 bound specifically to cdk5. Increased cyclin E/cdk2 expression was accompanied by increased DNA synthesis, whereas increased cyclin D1/cdk5 levels correlated with decreased DNA synthesis. In both growth- and differentiation-induced cells, cyclin D2 expression preceded the expression of cyclin D3, and a significantly larger amount of these cyclins was present in differentiation- as compared to proliferation-induced cells. In contrast, cdk4 and cdk6 were present at similar levels in the nuclear extracts from both growth- and differentiation-induced cells. These data show that, in ML-1 cells, the proliferation-associated progression from G1 to S, as well as the differentiation-associated transit from G1 to maturation is accompanied by the expression of specific cyclin/cdk pairs, comprising cdk2/cyclin E in growth and cdk5/cyclin D1 in differentiation.
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PMID:Differential expression of proteins regulating cell cycle progression in growth vs. differentiation. 915 Feb 73

Interleukin-6 (IL-6) promotes growth of human multiple myeloma (MM) cells via phosphorylation of retinoblastoma protein (pRB). We therefore examined the kinetics of cyclin-dependent kinase 4 (CDK4), p16INK4A, and pRB activation during IL-6-mediated patient MM cell growth compared with growth of IL-6 unresponsive patient plasma cell leukemia (PCL) cells. CDK4 protein was more strongly expressed in PCL cells than in MM cells. On the other hand, p16 protein was present in MM cells but undetectable in PCL cells. Interestingly, IL-6 induced peak proliferation of MM cells at days 1-3, with a return to baseline levels of DNA synthesis by days 6-9 in spite of replenishing IL-6. In these cells, IL-6 triggered a sustained increase in CDK4 by day 1 and a gradual increase in p16 to day 9. The progressive increase in p16 without further increments in CDK4 resulted in a shift from cyclin D2-CDK4/CDK6 binding at days 1-3 to p16-CDK4/CDK6 complex formation at days 6-9. Both phosphorylated pRB and dephosphorylated pRB were present initially in patient MM cells; IL-6 triggered a shift to phosphorylated pRB and G1 to S transition at days 1-3, with return to baseline levels of dephosphorylated pRB and related G1 growth arrest by day 9. No similar changes in CDK4, p16, or cell cycle profile were observed in IL-6 nonresponsive PCL cells. Our data therefore suggest a feedback mechanism in IL-6-mediated MM cell growth which is absent in IL-6 nonresponsive PCL cells.
Leukemia 1997 Nov
PMID:Role of CDK4 and p16INK4A in interleukin-6-mediated growth of multiple myeloma. 936 32

We previously reported that injection of recombinant granulocyte colony-stimulating factor (G-CSF) suppressed the development of leukemia in mice transplanted with C2M-A5 (C2M) myeloid leukemia cells and that the anti-leukemic effect of G-CSF was ascribed to the induction of apoptosis of C2M cells. These observations make a striking contrast with other previous reports on the biological activities of G-CSF. In the present study, in order to further clarify the G-CSF-induced apoptosis of C2M cells, we studied the effects of G-CSF on the cell cycle as well as the molecular events involving D-type cyclines and their cyclin-dependent kinases (cdk) in G-CSF-treated C2M cells. Cell cycle analysis revealed that G-CSF treatment of C2M cells resulted in accelerated entry from the first gap (G1) phase into the DNA synthesis (S) phase. Western blotting disclosed that G-CSF treatment resulted in down-regulation of cyclin D2 and cdk2 and up-regulation of cyclin D1 and cdk4. The reciprocal relationship between the up-regulation of cyclin D1 and down-regulation of cyclin D2 was closely associated with accelerated entry into S phase and subsequent apoptosis of C2M cells. These results suggest that G-CSF-induced apoptosis of C2M cells might be ascribed to imbalanced cell cycle progression due to deregulated expression of D-type cyclins and their cdks.
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PMID:Accelerated entry into S phase associated with up-regulation of cyclin D1 as a mechanism for granulocyte colony-stimulating factor (G-CSF)-induced apoptosis of murine myeloid leukemia cells. 961 17

Three D-type cyclins, cyclin D1, D2 and D3, belong to the G1 cyclin, which regulates the G1/S transition of the cell cycle, and feature highly homologous amino acid sequences. The cyclin D1 gene was found to be transcriptionally activated in B-lymphoid malignancies with t(11;14), but available information is limited regarding expression of cyclin D2 and D3 in hematopoietic malignancies. We examined the expressions of three D-type cyclins to investigate how these homologous genes are differentially used. Northern blot hybridization with densitometric analyses was performed to examine 64 cell lines and 159 patients with various hematopoietic malignancies. Among lymphoid malignancies, cyclin D1 overexpression was exclusively detected in B cell malignancies accompanied by a genetic event consisting of 11q13 chromosomal translocation, consisting of 13 of 19 (68%) patients with mantle cell lymphoma, two of 11 (18%) with B-chronic lymphocytic leukemia, and one of six (17%) with multiple myeloma. The cyclin D2 expression was significantly higher in T cell malignancies than in B cell malignancies (P = 0.003 for cell lines and P < 0.0001 for patient samples, respectively). In the T cell malignancies, cyclin D2 overexpression was predominantly recognized in those with mature phenotype. Furthermore, cyclin D2 expression was upregulated by phytohemagglutinin (PHA) stimulation of normal T-lymphocytes, suggesting that this simply represents the proliferation status of mature T cells. Although cyclin D3 was ubiquitously expressed, its expression was reduced in lymphoid malignancies with cyclin D1 or D2 overexpression. In myeloid leukemias, although three D-type type cyclins were differentially expressed, no preference for particular D-type cyclins was found. This selective usage of D-type cyclins in lymphoid malignancies suggests an existence of a regulatory mechanism among three D-type cyclins.
Leukemia 1999 Sep
PMID:Selective usage of D-type cyclins in lymphoid malignancies. 1048 83

Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent for adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis. Tax(1) is a 40-kDa phosphoprotein, predominantly localized in the nucleus of the host cell, which functions to transactivate both viral and cellular promoters. It seems likely that HTLV-1, through expression of the viral regulatory protein Tax(1), provides some initial alteration in cell metabolism predisposing the development of ATL. Here, we demonstrate that HTLV-1 infection in T-cell lines and patient samples causes overexpression of an early G(1) cyclin, cyclin D2. The transcriptional up-regulation of the cyclin D2 gene is due to activation of Tax on the cyclin D2 gene. More important, we find that overexpression of cyclin D2 is accompanied by acquisition of new partners such as cyclin-dependent kinase 2 (cdk2), cdk4, and cdk6 in infected cells. This is in contrast to uninfected T cells, where cyclin D2 associates only with cdk6. Functional effects of these cyclin-cdk complexes in infected cells are shown by hyperphosphorylation of Rb and histone H1, indicators of active progression into S phase as well as changes in cellular chromatin and transcription machinery. These studies link HTLV-1 infection with changes of cellular cyclin gene expression, hence providing clues to development of T-cell leukemia.
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PMID:Transcriptional up-regulation of the cyclin D2 gene and acquisition of new cyclin-dependent kinase partners in human T-cell leukemia virus type 1-infected cells. 1055 4

The transactivator protein Tax of human T-cell leukemia virus type I plays an important role in the development of adult T-cell leukemia probably through modulation of growth regulatory molecules including p16(INK4a). The molecular mechanism of leukemogenesis induced by Tax has yet to be elucidated. We analyzed Tax function in the cell cycle using an interleukin-2 (IL-2)-dependent human T-cell line (Kit 225) that can undergo cell cycle arrest at G(0)/G(1) phase by deprivation of IL-2. Tax activated endogenous E2F activity in IL-2-starved Kit 225 cells, resulting in activation of E2F site-carrying promoters of genes involved in G(1) to S phase transition in a cell type-dependent and p16(INK4a)-independent manner. The ability of Tax mutants to activate E2F coincided with that to activate nuclear factors kappaB and AT, sole expression of which, however, did not activate E2F, suggesting involvement of another pathway in activation of E2F. Introduction of Tax by a recombinant adenovirus induced cell cycle progression to G(2)/M phase in resting Kit 225 cells accompanied by endogenous cyclin D2 gene expression. Similarly, Tax-induced cell cycle progression was seen with peripheral blood lymphocytes prestimulated with phytohemagglutinin. Analyses with Tax mutants did not allow Tax-induced cell cycle progression to be differentiated from Tax-dependent activation of E2F, suggesting that Tax induces cell cycle progression presumably through activation of E2F. Nevertheless, infection with an E2F1-expressing virus, which is sufficient for induction of S phase in serum-starved fibroblasts, was not sufficient for either E2F activation or cell cycle progression in IL-2-starved Kit 225 cells, implying differential regulation of E2F activation and cell cycle progression in T-cells that is activated by Tax.
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PMID:Cell type-specific E2F activation and cell cycle progression induced by the oncogene product Tax of human T-cell leukemia virus type I. 1075 22


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