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)

This study was aimed to observe whether expressions of JAK2, STAT1, STAT5 proteins in indomethacin-treated CML cells involved in the proliferation inhibition of CML cells, and elucidate the pharmacological mechanism of indomethacin anti-leukemia. MTT assay and trypan blue dye exclusion test were used to detect the inhibitory effect of indomethacin on CML cells proliferation. JAK2, STAT1, STAT5 proteins were analyzed by Western blot; the subcellular distribution of STAT1, STAT5 were detected with indirect immunofluorescence technique. The results showed that indomethacin at >or= 400 micromol/L significantly inhibited the proliferation of CML cells and down-regulated the expression of STAT1, STAT5 protein, no JAK2 change was observed. STAT1 and STAT5 were located in cytoplasm. It is concluded that indomethacin inhibits the proliferation of CML cells and the mechanism may be related to down-regulated expression of STAT, or blockage of cells growth signals.
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PMID:[Proliferation-inhibiting effect of indomethacin on chronic myeliod leukemia cells is related to the supression of STAT signal transduction pathway]. 1563 56

Chronic myelomonocytic leukemia (CMML) comprises a spectrum of disease variably considered as a myelodysplastic (MDS) and/or myeloproliferative (MPD) disorder. Now classified by the WHO within a separate nosological group from MDS or MPD, the reality is that there is a dynamic of evolution through increasing monocyte counts in one-third of patients. The principal clinical difference between CMML and other MPD is the presence of ineffective hematopoiesis, manifesting as more frequent anemia and thrombocytopenia in CMML. A fundamental biological characteristic shared with MPD is progenitor hypersensitivity to growth factors, but the pathways mediating this likely differ, as does the lineage specificity. Activation of the STAT pathway in MPD contrasts with frequent RAS pathway activation in CMML. Therapy of CMML is unsatisfactory, with the median age dictating that supportive care and control of myeloproliferation remains the mainstay for the majority. Intensive chemotherapy alone is of little benefit, and stem cell transplantation is the only curative modality in the small number of eligible patients, although outcome remains suboptimal. A deeper understanding of the biological basis of CMML may lead to targeted therapy analogous to the evolving management of MPD best exemplified for chronic myeloid leukemia.
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PMID:Chronic myelomonocytic leukemia: lost in classification? 1614 5

To study the gene expression profile in K562 cells treated by IFN-alpha, so as to provide some information about the potential mechanism of IFN-alpha curing CML, the changes of gene expression were examined with the DNA array in K562 cells before and after treatment with IFN-alpha. The results showed that no gene expression difference more than 2.5 times in K562 cells was found on the first day after treatment with IFN-alpha (200 U/ml), then the genes significant expression difference increased step by step, and reached the peak on the forth day. In all examined genes, 97 genes significant expression difference were detected, 86.60% (84/97) gene of interest out of those gene were up-regulated, 13.40% (13/97) were down-regulated. In these 97 genes with significant expression difference, cell regulator protein genes accounted to 23.71% (23/97), surface receptor genes 14.43% (14/97), oncogenes and tumor suppressors 11.34% (11/97), extracellular communication proteins 9.28% (9/97), cell adhesion molecular genes 8.25% (8/97) and the other genes accounted to 32.99% (32/97). JAK1 was up-regulated to 3.78 times, JAK2 to 15.43, STAT1 and STAT2 were up-regulated to 11.98 and 8.11 times respectively, and these genes are components of JAK-STAT pathway. The number of different genes began to decrease on the fifth day. There were still 9 genes that had expression difference more than 3 times on the twenty-first day. It is concluded that when concentration of IFN-alpha was 200 U/ml, the forth day should be considered as the best time to examine change of gene expression in K562 cells treated by IFN-alpha. IFN-alpha realizes its biological functions through the JAK-STAT pathways and it may be one of the mechanisms for curing CML with IFN-alpha.
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PMID:[Gene expression profile in K562 cells treated by interferon alpha]. 1627 35

Indomethacin (IN) can inhibit cyclooxygenase activity and is considered to exert antitumor action in a variety of cancer cells. In the present study, we investigated the underlying mechanism of its antiproliferative effect on chronic myeloid leukemia (CML) cells. We studied the role of signal transducer and activator of transcription 1 or 5 (STAT(1) or STAT(5)) and Bcl-X(L) proteins in IN-induced proliferative inhibition on CML cells. Both K562 cells and fresh bone marrow mononuclear cells from five CML patients were exposed to IN. Cell proliferation was determined by MTT assay. The expression of JAK(2), STAT(1), STAT(5), and Bcl-X(L) proteins was probed with Western blotting. The level of phosphorylated STAT(1) (p-STAT(1)) or STAT(5) (p-STAT(5)) proteins was determined by coimmunoprecipitation combined with Western blotting. Intracellular localizations of both STAT(1)/STAT(5) and p-STAT(1)/p-STAT(5) were observed by indirect immunofluorescence assay. Our results showed that IN could inhibit the proliferation of CML cells in a dose-dependent manner (36-288 microg/ml). The expression of STAT(1) and STAT(5) was suppressed by IN both in a concentration-dependent manner and a time-dependent (0-36 h) manner. The levels of p-STAT(1) and p-STAT(5) were down-regulated by IN. A similar result was obtained for Bcl-X(L) protein expression. The intracellular fluorescence signals representing STAT(1)/STAT(5) and p-STAT(1)/p-STAT(5) were obviously weakened by IN. In contrast with IN, granulocyte-macrophage colony-stimulating factor could significantly promote the growth of CML cells and up-regulate the expression of both STAT(1)/STAT(5) and p-STAT(1)/p-STAT(5). This data indicated that IN is able to suppress the proliferation of CML cells, and the mechanism is associated with the inhibition of STATs/ Bcl-X(L) signal transduction pathway.
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PMID:Antiproliferative effect of indomethacin on CML cells is related to the suppression of STATs/Bcl-XL signal pathway. 1657 23

IL-2 plays a critical role in the maintenance of CD4+CD25+ FOXP3(+) regulatory T cells (Tregs) in vivo. We examined the effects of IL-2 signaling in human Tregs. In vitro, IL-2 selectively up-regulated the expression of FOXP3 in purified CD4+CD25+ T cells but not in CD4+CD25- cells. This regulation involved the binding of STAT3 and STAT5 proteins to a highly conserved STAT-binding site located in the first intron of the FOXP3 gene. We also examined the effects of low-dose IL-2 treatment in 12 patients with metastatic cancer and 9 patients with chronic myelogenous leukemia after allogeneic hematopoietic stem cell transplantation. Overall, IL-2 treatment resulted in a 1.9 median fold increase in the frequency of CD4+CD25+ cells in peripheral blood as well as a 9.7 median fold increase in FOXP3 expression in CD3+ T cells. CD56+CD3- natural killer (NK) cells also expanded during IL-2 therapy but did not express FOXP3. In vitro treatment of NK cells with 5-aza-2'-deoxycytidine restored the IL-2 signaling pathway leading to FOXP3 expression, suggesting that this gene was constitutively repressed by DNA methylation in these cells. Our findings support the clinical evaluation of low-dose IL-2 to selectively modulate CD4+CD25+ Tregs and increase expression of FOXP3 in vivo.
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PMID:IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. 1664 71

Overcoming imatinib mesylate (IM) resistance and disease persistence in patients with chronic myeloid leukemia (CML) is of considerable importance to the issue of potential cure. Here we asked whether autocrine signaling contributes to survival of BCR/ABL+ cells in the presence of IM and nilotinib (NI; AMN107), a novel, more selective Abl inhibitor. Conditioned media (CM) of IM-resistant LAMA84 cell clones (R-CM) was found to substantially protect IM-naive LAMA cells and primary CML progenitors from IM- or NI-induced cell death. This was due to an increased secretion of the granulocyte-macrophage colony-stimulating factor (GM-CSF), which was identified as the causative factor mediating IM resistance in R-CM. GM-CSF elicited IM and NI drug resistance via a BCR/ABL-independent activation of the janus kinases 2 (JAK-2)/signal transducer and activator of transcription 5 (STAT-5) signaling pathway in GM-CSF receptor alpha receptor (CD116)-expressing cells, including primary CD34+/CD116+ GM progenitors (GMPs). Elevated mRNA and protein levels of GM-CSF were detected in IM-resistant patient samples, suggesting a contribution of GM-CSF secretion for IM and NI resistance in vivo. Importantly, inhibition of JAK-2 with AG490 abrogated GM-CSF-mediated STAT-5 phosphorylation and NI resistance in vitro. Together, adaptive autocrine secretion of GM-CSF mediates BCR/ABL-independent IM and NI resistance via activation of the antiapoptotic JAK-2/STAT-5 pathway. Inhibition of JAK-2 overcomes GM-CSF-induced IM and NI progenitor cell resistance, providing a rationale for the application of JAK-2 inhibitors to eradicate residual disease in CML.
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PMID:Adaptive secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) mediates imatinib and nilotinib resistance in BCR/ABL+ progenitors via JAK-2/STAT-5 pathway activation. 1709 Jun 51

JAK2V617F, a somatic gain-of-function mutation involving the JAK2 tyrosine kinase gene, occurs in nearly all patients with polycythemia vera (PV) but also in a variable proportion of patients with other myeloid disorders; mutational frequency is estimated at approximately 50% in both essential thrombocythemia (ET) and myelofibrosis (MF), up to 20% in certain subcategories of atypical myeloproliferative disorder (atypical MPD), less than 3% in de novo myelodysplastic syndrome (MDS) or acute myeloid leukemia, and 0% in chronic myeloid leukemia (CML). Accordingly, there is now molecular justification for grouping PV, ET, and MF together in a distinct MPD category (i.e., classic, BCR-ABL(-) MPD) that is separate from chronic myeloid leukemia (CML), MDS, and atypical MPD. To date, JAK2V617F has not been described in patients with reactive myeloproliferation, lymphoid disorders, or solid tumor. Therefore, the presence of JAK2V617F strongly suggests an underlying MPD and it is therefore reasonable to consider JAK2V617F-based laboratory tests for the evaluation of polycythemia, primary thrombocytosis, unexplained leukocytosis, bone marrow fibrosis, or abdominal vein thrombosis. Current information on disease-specific prognostic relevance of JAK2V617F is inconclusive and confounded by inter-study differences in the performance of mutation screening assays. Regardless, the discovery of JAK2V617F has reinforced the pathogenetic contribution of JAK-STAT signaling in MPD and identifies JAK2 as a valid drug target.
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PMID:Classification, diagnosis and management of myeloproliferative disorders in the JAK2V617F era. 1712 67

The recently described JAK2 V617F mutation, present in a substantial proportion of nonchronic myelogenous leukemia chronic myeloproliferative disorders (non-CML CMPDs), is changing the way we conceptualize and diagnose these diseases. We hypothesized that the activation of this tyrosine kinase might result in activation of downstream mediators such as STAT5, which would be detectable in bone marrow biopsies. We examined the expression of activated STAT5 (nuclear phospho-STAT5) in 73 bone marrow biopsies from patients with CMPDs [20 essential thrombocythemia (ET), 26 chronic idiopathic myelofibrosis (CIMF), and 27 polycythemia vera] and 39 controls. We compared the results with the JAK2 mutational status and clinical parameters. The frequency of the JAK2 V617F was 73% (85% in PV, 65% in ET, and 65% in CIMF). All patients with the JAK2 V617F showed abnormal nuclear megakaryocytic phospho-STAT5 (nMEG pSTAT5) expression. In the JAK2 wild-type group, nMEG pSTAT5 was observed in 2/7 ET, and 3/9 CIMF patients. nMEG pSTAT5 staining was 100% sensitive and 88% specific for JAK2 V617F. Clinically, nMEG pSTAT5+ patients seemed to require cytoreductive therapy more often than those without nMEG p-STAT expression. pSTAT5 immunohistochemistry is a useful diagnostic test in bone marrow biopsies from suspected non-CML CMPD patients. It identifies most of the patients with the JAK2 V617F but also other JAK2 wild-type CMPD patients. The presence of nMEG pSTAT5 in a subset of CMPD patients lacking the mutation suggests that alternate tyrosine kinase/phosphatase pathways may be involved and warrant further investigation. Phosphoprotein detection represents a new area for diagnostic pathology that exploits specific functional characteristics of cells within the context of a tissue section.
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PMID:Bone marrow phospho-STAT5 expression in non-CML chronic myeloproliferative disorders correlates with JAK2 V617F mutation and provides evidence of in vivo JAK2 activation. 1725 68

SOCS-1, an important protein in the JAK/STAT pathway, has a role in the down stream of BCR-ABL protein kinase. We investigated 56 CML patients and 16 controls for the methylation status of SOCS-1 gene promoter and Exon 2 regions. Exon 2 was found to be methylated in 58.9% of the patients and 93.8% of the controls [P = 0.020, OR = 0.121(0.015-0.957)%95CI]. The promoter region was found unmethylated in all patient samples and controls. Although previous studies revealed a relation between SOCS1 gene Exon-2 hypermethylation and CML development or progression, the results of this study showed no such correlation. On the contrary, our results might be indicating hypomethylation in CML patients, this hypothesis need to be studied in larger study population.
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PMID:The SOCS-1 gene methylation in chronic myeloid leukemia patients. 1731 16

The chimeric bcr-abl gene encodes a constitutively active tyrosine kinase that leads to abnormal transduction of growth and survival signals leading to chronic myeloid leukemia (CML). According to our previous observations, in vitro differentiation of several erythroid cell lines is accompanied by the downregulation of extracellular signal-regulated kinases (ERK)1/2 mitogen-activated protein kinase (MAPK) activities. In this work we investigated whether ERKs have a decisive role in either the erythroid differentiation process or apoptosis of bcr-abl+ K562 cells by means of direct (MEK1/2 inhibitor UO126) and indirect (reduced Bcr-Abl function) inhibition of their activities. We found that both Gleevec and UO126 induced hemoglobin expression. Gleevec treatment reduced the phosphorylation of Bcr-Abl, ERK and STAT-5 for up to 24 h, decreased Bcl-XL levels, and induced caspase-3-dependent apoptosis. In contrast, UO126 treatment resulted in only a transient decrease of ERK activity and did not induce cell death. For studying the effect of reduced Bcr-Abl function on erythroid differentiation at the level of the bcr-abl transcript, we applied the siRNA approach. Stable degradation of bcr-abl mRNA was achieved by using a retroviral vector with enhanced green fluorescent protein (EGFP) reporter. Despite a high (>90%) transduction efficiency we detected only a transient decrease in Bcr-Abl protein and in phosphorylated ERK1/2 levels. This transient change in Bcr-Abl signaling was sufficient to induce hemoglobin expression without significant cell death. These results suggest that by transiently reducing Bcr-Abl function it is possible to overcome the differentiation blockade without evoking apoptosis in CML cells and that reduced ERK activity may have a crucial role in this process.
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PMID:Reduction of Bcr-Abl function leads to erythroid differentiation of K562 cells via downregulation of ERK. 1738 79


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