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)

CD4(+)CD25(+) regulatory T cells have been characterized as a critical population of immunosuppressive cells. They play a crucial role in cancer progression by inhibiting the effector function of CD4(+) or CD8(+) T lymphocytes. However, whether regulatory T lymphocytes that expand during tumor progression can modulate dendritic cell function is unclear. To address this issue, we have evaluated the inhibitory potential of CD4(+)CD25(+) regulatory T cells from mice bearing a BCR-ABL(+) leukemia on bone marrow-derived dendritic cells. We present data demonstrating that CD4(+)CD25(+)FoxP3(+) regulatory T cells from tumor-bearing animals impede dendritic cell function by down-regulating the activation of the transcription factor NF-kappaB. The expression of the co-stimulatory molecules CD80, CD86 and CD40, the production of TNF-alpha, IL-12, and CCL5/RANTES by the suppressed DC is strongly down-regulated. The suppression mechanism requires TGF-beta and IL-10 and is associated with induction of the Smad signaling pathway and activation of the STAT3 transcription factor.
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PMID:Tumor-derived CD4(+)CD25(+) regulatory T cell suppression of dendritic cell function involves TGF-beta and IL-10. 1661 96

The aim is to clarify expression changes of ERK1/2, STAT3 and SHP-2 in bone marrow cells from gamma-ray induced leukemia mice. A mouse model of gamma-ray induced leukemia was produced, and by means of quantitative real-time PCR, immunoprecipitation, Western blotting and electrophoretic mobility shift assays (EMSA), the expression of mRNA and protein, phosphorylation level, and protein activity of ERK1/2, STAT3 and SHP-2 in bone marrow cells were investigated in these mice. The results indicated that mRNA and protein expressions of ERK1/2 were upregulated, with significant increase of phosphorylation level and protein activity, but with insignificant differences in mRNA and protein expressions, phosphorylation level and protein activity of STAT3 and SHP-2 in bone marrow cells from gamma-ray induced leukemia mice compared to the radiation/tumor-free or control mice. It is concluded that in the pathogenesis of gamma-ray induced leukemia in Balb/C mice, activated ERK1/2 pathway may play a role, without involving STAT3 pathway; meanwhile, SHP-2 exerts no regulative effect on pathways of Ras-ERK1/2 and JAK-STAT.
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PMID:Expression changes of ERK1/2, STAT3 and SHP-2 in bone marrow cells from gamma-ray induced leukemia mice. 1681 38

This study was aimed to investigate the activation of P38MAPK/STAT3 and expression of telomerase reverse transcriptase during sodium nitroprusside (SNP) inducing apoptosis of human leukemia cell line K562 and to explore the molecular mechanisms of SNP-inducing apoptosis in K562 cells. The K562 cell were treated with different concentrations of SNP and were cultured for different time. Cell apoptosis was analysed by cell morphology, DNA agarose gel electrophoresis, DNA content, and Annexin-V/PI labeling method. The TdT-mediated dUTP nick end labeling (TUNEL) assay was used to quantitate the in situ cell apoptosis. The expressions of phosphorylated p38MAPK or STAT3 were analysed by flow cytometry, while the expression of hTERT mRNA in transcriptional level was measured by fluorescence quantitative RT-PCR. The results showed that SNP inhibited K562 cell growth. The K562 cell apoptosis was confirmed by typical cell morphology and DNA fragment, peak of sub-G1 phase, TUNEL and Annexin-V/PI labeling. A majority of K562 cells were arrested in G0/G1 phase. After treatment with SNP at 0.5-3.0 mmol/L, the expression of phosphorylated-P38MAPK and phosphorylated-STAT3 increased first and decreased afterwards. Incubation of K562 cell with SNP (2 mmol/L) could increase the expression of phosphorylated-P38MAPK and phosphorylated-STAT3 at 12 hours and 24 hours respectively, and down-regulated at 72 hours and 48 hours. SNP could decrease the expression of hTERT-mRNA in time-and dose-dependent manner. It is concluded that SNP can significantly induce K562 cells apoptosis, its mechanism may be related to the activation of P38MAPK and suppression of phosphorylated-STAT3 and hTRET-mRNA.
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PMID:[Effects of sodium nitroprusside on P38MAPK/STAT3 activation and telomerase reverse transcriptase mRNA expression in inducing apoptosis of K562 cell line]. 1692

Signal transducers and activators of transcription (STATs) play important roles in numerous cellular events as for example differentiation, inflammation or immune response. Furthermore, constitutive STAT activation can be observed in a high number of tumors. In our hands, curcumin treatment induced a decrease of nuclear STAT3, -5a and -5b, without affecting neither STAT1, nor the phosphorylation state of STAT1, -3 or -5 in the K562 cell line. Most interestingly, the decrease of nuclear STAT5a and -5b after curcumin treatment was accompanied by an increase of truncated STAT5 isoforms, indicating that curcumin is able to induce the cleavage of STAT5 into its dominant negative variants lacking the STAT5 C-terminal region. Interferon (IFN)-beta and -gamma treatment induced IFN-stimulated responsive element (ISRE) transcriptional activity, which was efficiently inhibited by curcumin pre-treatment. In parallel, IFN-gamma treatment induced an increase of the amount of nuclear STAT1 and -3, as well as their phosphorylated isoforms. Again, curcumin pre-treatment inhibited these increases. Finally, curcumin treatment inhibited Jak2 mRNA expression as well as cyclin D1 and v-src gene expression in K562 chronic leukaemia cells.
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PMID:Curcumin regulates signal transducer and activator of transcription (STAT) expression in K562 cells. 1695 22

STATs are believed to play key roles in normal and abnormal cell function. In the present work, we investigated the role of STATs in an IL-2-responsive human lymphoblastic lymphoma-derived cell line, YT. Only STAT3 was found constitutively tyrosine phosphorylated, but not other STATs. Hyperactive STAT3 was not attributable to a pre-existing intermediate affinity IL-2R complex and/or hyperactive Jak activity. Depletion of STAT3 protein expression reduced tumor cell viability with protracted kinetics (72-96 h), while TUNEL assays demonstrated cell death occurred via apoptosis. Interestingly, depletion of STAT5 in this same tumor induced more pronounced cell death compared with STAT3 depletion (24 h). Although IL-2 was able to rescue STAT3-depleted cells from death, it could not compensate for the loss of STAT5. To determine the prosurvival function of STAT3 vs STAT5 within the same tumor model, genes were profiled in STAT3- or STAT5-depleted YT cells by apoptosis-specific microarrays. Several differentially expressed genes were identified. Interestingly, those genes involved in NF-kappaB regulation, such as TNFR-associated factors 2 and 5 and B cell leukemia/lymphoma 10, were readily decreased upon STAT5, but not STAT3, depletion as validated by quantitative RT-PCR. These results suggest that STAT5 and, to a lesser extent, hyperactive STAT3 provide preferential and critical cell survival signals for certain human lymphoid tumors, indicating that nonhyperactive STATs should be considered as therapeutic targets for abrogating tumorigenesis.
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PMID:A preferential role for STAT5, not constitutively active STAT3, in promoting survival of a human lymphoid tumor. 1701 86

Mutations in the granulocyte colony-stimulating factor receptor (G-CSF-R) gene leading to a truncated protein have been identified in a cohort of neutropenia patients highly predisposed to acute myeloid leukemia. Such mutations act in a dominant manner resulting in hyperproliferation but impaired differentiation in response to G-CSF. This is due, at least in part, to defective internalization and loss of binding sites for several negative regulators, leading to sustained receptor activation. However, those signaling pathways responsible for mediating the hyperproliferative function have remained unclear. In this study, analysis of an additional G-CSF-R mutant confirmed the importance of residues downstream of Box 2 as important contributors to the sustained proliferation. However, maximal proliferation correlated with the ability to robustly activate signal transducer and activator of transcription (STAT) 5 in a sustained manner, whereas co-expression of dominant-negative STAT5, but not dominant-negative STAT3, was able to inhibit G-CSF-stimulated proliferation from a truncated receptor. Furthermore, a Janus kinase (JAK) inhibitor also strongly reduced the proliferative response, whereas inhibitors of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) or phosphatidylinositol (PI) 3-kinase reduced proliferation to a lesser degree. These data suggest that sustained JAK2/STAT5 activation is a major contributor to the hyperproliferative function of truncated G-CSF receptors, with pathways involving MEK and PI 3-kinase playing a reduced role.
Leukemia 2006 Dec
PMID:Multiple pathways contribute to the hyperproliferative responses from truncated granulocyte colony-stimulating factor receptors. 1706 93

The purpose of this study was to explore the effect of N, N'-di-(m-methylphenyi)-3, 6-dimethyl-1, 4-dihydro-1, 2, 4, 5-tetrazine-1, 4-dicarboamide (ZGDHu-1) on proliferation, differentiation and apoptosis in NB4 human leukemia cell line and its possible mechanism. Different concentrations of ZGDHu-1 and the different time of cultivation were used to treat NB4 cells. The proliferation inhibition of NB4 cells was analysed by cell counting, alive cell count, MTT assay. Cell apoptosis was determined by cell morphology, DNA agarose gel electrophoresis, DNA content, Annexin-V/PI and Hoechst 33258 labeling method. The analysis of cell morphological change, expression of CD11b, CD13 and NBT reduction were performed to evaluate the differentiation of NB4 cells. The expressions of bcl-2, bax and phosphorylated p38MAPK or STAT3 were detected by flow cytometry. While the expression of hTERT mRNA in transcriptional level was measured by fluorescence quantitative RT-PCR. The results showed that ZGDHu-1 could inhibit NB4 cell proliferation viability within a certain range of treating time and does, IC(50) values at 48 and 72 hours were 450 ng/ml and 200 ng/ml respectively. A majority of NB4 cells were arrested in G(2/M) phase and a progressive decline of cells was seen in G(0/1). The NB4 cells apoptosis was confirmed by cell typical cell morphology, DNA fragments and sub-G(1) phase peak as well as Hoechst33258 and Annexin-V/PI labeling method with a time-dose-related manner. The morphology of NB4 cells cultured in the presence of 2 - 100 ng/ml ZGDHu-1 for three days was more mature with higher NBT positivity and expressions of CD11b and CD13 than those in control. The expression of phosphor-p38MAPK and bax was increased while phosphor-STAT3 and bcl-2 were unchanged by the treatment of ZGDHu-1. ZGDHu-1 could decrease the expression of hTERT-mRNA in a dose-dependent manner. It is concluded that ZGDHu-1 can inhibit proliferation, induce differentiation and apoptosis of NB4 cells. The mechanism may be associated with up-regulation of bax expression, enhancement of phosphor-p38MAPK activation and inhibition of hTERT-mRNA.
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PMID:[Effects of N, N'-Di-(m-methylphenyi)-3, 6-dimethyl-1, 4-dihydro-1, 2, 4, 5-tetrazine-1, 4-dicarboamide on proliferation, apoptosis and differentiation of NB4 leukemia cells in vitro]. 1709 81

Signal transduction pathways integrate a variety of microenvironmental cues to guide cell function by regulating gene transcription, cell cycle status, growth, and differentiation. It is well established that perturbation of these processes plays a key role in hematologic malignancies including lymphomas and chronic and acute lymphocytic leukemias. Altered intracellular signaling pathways have been proposed to mediate many biological properties of T cell large granular lymphocytic leukemia (T-LGL), a disorder characterized by a clonal proliferation of CD8 T cells resulting in immune-mediated cytopenias, most commonly neutropenia. Since T-LGL offers a unique opportunity to study signal transduction in the pathologic clonal cytotoxic T cell (CTL) compared to normal CTL, we have investigated a potential imbalance in T-LGL pro-survival signaling to define the mechanisms underlying the semi-autonomous proliferation leading to leukemia. Increased activity of the PI3K-AKT signaling axis in T-LGL cells appears to operate in conjunction with or parallel to increased STAT3 activation in these cells to inhibit the apoptotic program. Thus, the ability to define pathophysiology at the molecular level opens new avenues for targeted therapeutics.
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PMID:Pathophysiology defined by altered signal transduction pathways: the role of JAK-STAT and PI3K signaling in leukemic large granular lymphocytes. 1717 39

Stem cell factor (SCF) has important roles in the proliferation and differentiation of hematopoietic stem cells. The complex of c-Kit and its ligand SCF induce hematopoiesis, melanogenesis, and gametogenesis. However, the mechanism by which SCF induces cell proliferation in the human megakaryoblastic leukemia cell line, MO7e, and the signaling molecules involved, especially in downstream signaling of c-Kit, remain unclear. Here, we show that pharmacological inhibition of the PI3K pathway inhibits SCF/c-Kit signaling and cell proliferation. In addition, we find that the Shc/PDK1/PKC/Akt/c-raf signaling cascade is essential for SCF/c-Kit signal pathway. Our results also suggest that ERK5 is activated and translocated to the nucleus, activating CREB and STAT3. Interestingly, chrysin shuts down the SCF/c-Kit complex-induced signaling cascade. Taken together, these studies give additional insight into the molecular mechanism of SCF/c-Kit-induced cell proliferation and its inverse agonist, chrysin. Finally, these findings enhance our understanding of MO7e cell proliferation.
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PMID:Chrysin inhibited stem cell factor (SCF)/c-Kit complex-induced cell proliferation in human myeloid leukemia cells. 1749 88

The FIP1-like-1 (FIP1L1)-platelet-derived growth factor receptor-alpha (FIP1L1-PDGFR-alpha) fusion kinase causes hypereosinophilic syndrome (HES) in a defined subset of patients. Imatinib mesylate is a potent inhibitor of ABL but also of PDGFR-alpha, and has been associated with durable hematologic responses in patients with HES. However, development of mutations in the tyrosine kinase domain may hamper the activity of tyrosine kinase inhibitors (TKIs), which suggests that novel agents are warranted to prevent or overcome resistance. We evaluated the efficacy of the novel TKI EXEL-0862 in FIP1L1-PDGFR-alpha-expressing cell lines and in cells from a patient with HES harboring the FIP1L1-PDGFR-alpha gene. EXEL-0862 inhibited the proliferation of EOL-1 and imatinib-resistant T674I FIP1L1-PDGFR-alpha-expressing cells and resulted in potent inhibition of the phosphorylation of PDGFR-alpha and downstream proteins STAT3 and Erk1/2, both in vitro and ex vivo. Moreover, EXEL-0862 induced apoptotic death in EOL-1 cells and imatinib-resistant T674I FIP1L1-PDGFR-alpha-expressing cells, and resulted in significant downregulation of the antiapoptotic protein Mcl-1 through a caspase-dependent mechanism. Our data establish EXEL-0862 as a solid candidate for the targeted treatment of patients with FIP1L1-PDGFR-alpha-positive HES.
Leukemia 2007 Jul
PMID:The novel tyrosine kinase inhibitor EXEL-0862 induces apoptosis in human FIP1L1-PDGFR-alpha-expressing cells through caspase-3-mediated cleavage of Mcl-1. 1749 75


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