Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated tyrosine phosphorylation of proteins in primary human leukemia cells stimulated by granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), interleukin-3 (IL-3), tumor necrosis factor (TNF), thrombopoietin (TPO) and phorbol myristate acetate (PMA) in 61 patients with acute myeloid leukemia (AML), nine patients with chronic myeloid leukemia (CML) in blastic crisis and four patients in chronic phase, and compared these data of leukemia with those of normal human immature hematopoietic cells. These cytokines and PMA induced tyrosine phosphorylation of proteins in a manner characteristic for each cytokine or PMA in AML cells. G-CSF, GM-CSF and IL-3 frequently phosphorylated p92, p80, p70, p44 and p42. p95 was frequently phosphorylated by G-CSF, and was phosphorylated in one third of the cases by TPO. On the other hand, TNF selectively induced tyrosine phosphorylation of p42, and PMA selectively induced that of p44 and p42. In marked contrast to AML cells, CML cells responded poorly to cytokines with protein tyrosine phosphorylation, and normal human bone marrow mononuclear cells and CD34-positive cells also showed poor response to cytokines. The results of the immunoprecipitation studies showed tyrosine phosphorylation of signal transducers and activators of transcription (Stat) 5 induced by G-CSF, GM-CSF, IL-3 and/or TPO in six cases, that of extracellular signal-regulated kinase (ERK) by GM-CSF in two cases and that of p38 by TNF in three cases. Intracellular amount of Stat5 was markedly increased in AML cells compared with that in CML cells and normal human bone marrow cells. whereas intracellular amount of ERK and p38 was uniformly abundant in both leukemic and normal cells. These results show cytokine-specific and amplified tyrosine phosphorylation of proteins in AML cells and suggest that amplified response might, at least in part, result from the increased amount of signaling molecules such as Stat5.
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PMID:Tyrosine phosphorylation of proteins in primary human myeloid leukemia cells stimulated by cytokines: analysis of the frequency of phosphorylation, and partial identification and semi-quantification of signaling molecules. 988 38

RAGE (receptor for advanced glycation end products) is a multiligand cell surface molecule of the immunoglobulin superfamily. It was originally described as a receptor for protein adducts formed by glycoxidation (AGEs) that accumulate in diseases such as diabetes and renal failure. Performing RT-PCR and Western blot analysis we intended to determine RAGE expression in the human colon adenocarcinoma cell line Caco-2. Moreover, Caco-2 cells were incubated in the presence of AGEs. Since RAGE ligation triggers the p21(ras) signal transduction pathway the activation state of p44/42 (ERK1/2) MAP kinases was determined. Here we demonstrate for the first time that Caco-2 cells express RAGE and that administration of the food-derived casein-linked AGE N(epsilon)-(carboxymethyl)lysine (Cas-CML) results in Caco-2 p44/42 (ERK1/2) MAP kinase activation.
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PMID:RAGE expression and AGE-induced MAP kinase activation in Caco-2 cells. 1170 25

Investigating the cellular effects of food compounds formed by heat treatment during processing, we recently demonstrated the expression of the receptor for advanced glycation endproducts (RAGE) and the p44/42 MAP kinase activation by casein-N(epsilon )-(carboxymethyl)lysine (casein-CML), a food-derived AGE, in the intestinal cell line Caco-2. In this work, we report a Caco-2 p44/42 MAP kinase activation by bread crust and coffee extract. After identification, quantification, and synthesis of two key compounds formed in association with the process-induced heat impact applied to bread dough and coffee beans, those compounds, namely the AGE pronyl-glycine and the non-AGE N-methylpyridinium, were also demonstrated for the first time to activate the p44/42 MAP kinase through binding to RAGE in Caco-2 cells. Blocking of RAGE by an antagonistic antibody and expression of C-terminally truncated RAGE resulted in a reduced Caco-2- and HEK-293-MAP kinase activation. These findings unequivocally point to a RAGE-mediated activating effect of chemically defined food-derived, thermally generated products, both, AGEs and non-AGEs, on cellular signal transduction pathways involved in inflammatory response and cellular proliferation.
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PMID:RAGE-mediated MAPK activation by food-derived AGE and non-AGE products. 1250 85

The BCR/ABL tyrosine kinase inhibitor, imatinib, has shown substantial effects in blast crises of chronic myelogenous leukemia. However, most patients relapse after an initial clinical response, indicating that drug resistance is a major problem for patients being treated with imatinib. In this study, we generated a new imatinib-resistant BCR/ABL-positive cell line, KCL22/SR. The 50% inhibitory concentration of imatinib was 11-fold higher in KCL22/SR than in the imatinib-sensitive parental cell line, KCL22. However, KCL22/SR showed no mutations in the BCR/ABL gene and no increase in the levels of BCR/ABL protein and P-glycoprotein. Furthermore, the level of phosphorylated BCR/ABL protein was suppressed by imatinib treatment, suggesting that mechanisms independent of BCR/ABL signaling are involved in the imatinib resistance in KCL22/SR cells. DNA microarray analyses demonstrated that the signal transduction-related molecules, RAS p21 protein activator and RhoA, which could affect Ras signaling, and a surface tumor antigen, L6, were upregulated, while c-Myb and activin A receptor were downregulated in KCL22/SR cells. Furthermore, imatinib treatment significantly suppressed the level of phosphorylated p44/42 in KCL22 cells but not in KCL22/SR cells, even when BCR/ABL was inhibited by imatinib. These results suggest that various mechanisms, including disturbance of Ras-mitogen-activated protein kinase signaling, are involved in imatinib resistance.
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PMID:Analysis of gene expression profiles in an imatinib-resistant cell line, KCL22/SR. 1274 26

Oxidative and carbonyl stress leads to generation of N(epsilon)-carboxymethyllysine-modified proteins (CML-mps), which are known to bind the receptor for advanced glycation end products (RAGE) and induce nuclear factor (NF)-kappaB-dependent proinflammatory gene expression. To determine the impact of CML-mps in vivo, RAGE-dependent sustained NF-kappaB activation was studied in resection gut specimens from patients with inflammatory bowel disease. Inflamed gut biopsy tissue demonstrated a significant up-regulation of RAGE and increased NF-kappaB activation. Protein extracts from the inflamed zones, but not from noninflamed resection borders, caused perpetuated NF-kappaB activation in cultured endothelial cells, which was mediated by CML-mps including CML-modified S100 proteins. The resulting NF-kappaB activation, lasting 5 days, was primarily inhibited by either depletion of CML-mps or by the addition of sRAGE, p44/42 and p38 MAPKinase-specific inhibitors. Consistently, CML-mps isolated from inflamed gut areas and rectally applied into mice caused NF-kappaB activation, increased proinflammatory gene expression, and histologically detectable inflammation in wild-type mice, but not in RAGE-/- mice. A comparable up-regulation of NF-kappaB and inflammation on rectal application of CML-mps was observed in IL-10-/- mice. Thus, CML-mps generated in inflammatory lesions have the capacity to elicit a RAGE-dependent intestinal inflammatory response.
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PMID:Posttranslationally modified proteins as mediators of sustained intestinal inflammation. 1700 81

Deciphering the BCR-ABL-independent signaling exploited in chronic myeloid leukemia (CML) progression is an important aspect in cancer stem-cell biology. CML stem-cell compartment is dynamic as it progresses to terminal blast crisis where myeloid and lymphoid blasts fail to differentiate. We demonstrate cross-regulation of signaling network involving Sonic hedgehog (Shh), Wnt, Notch and Hox for the inexorable blastic transformation of CD34(+) CML cells. Significant upregulation in Patched1, Frizzled2, Lef1, CyclinD1, p21 (P < or =0.0002) and downregulation of HoxA10 and HoxB4 (P< or =0.0001) transcripts in CD34(+) cells distinguish blast crisis from chronic CML. We report Shh-dependent Stat3 activation orchestrates these mutually interconnected signaling pathways. Stimulation of CD34(+) CML cells with either soluble Shh or Wnt3a did not activate Akt or p44/42-mitogen activated protein kinase (MAPK) pathways. Interestingly, unlike dominant negative Stat3beta, introduction of constitutive active Stat3 in CD34(+) CML cells induces cross-regulation in gene expression. Additionally, Shh and Wnt3a-dependent regulation of cyclin-dependent kinase inhibitors (CDKI) in CML suggests their role in the network. Taken together, our findings propose that deregulation in the form of hyperactive Shh and Wnt with repressed Notch and Hox pathways involving Stat3, Gli3, beta-catenin, CyclinD1, Hes1, HoxA10 and p21 might act synergistically to form an important hub in CML progression.
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PMID:Deregulation and cross talk among Sonic hedgehog, Wnt, Hox and Notch signaling in chronic myeloid leukemia progression. 1736 Dec 18

The olfactory receptor (OR) family was found to be expressed mainly in the nasal epithelium. In the last two decades members of the OR family were detected to be functional expressed in different parts of the human body such as in liver, prostate or intestine cancer cells. Here, we detected the expression of several ORs in the human chronic myelogenous leukemia (CML) cell line K562 and in white blood cells of clinically diagnosed acute myeloid leukemia (AML) patients by RT-PCR and next-generation sequencing. With calcium-imaging, we characterized in greater detail the cell biological role of one OR (OR2AT4) in leukemia. In both cell systems, the OR2AT4 agonist Sandalore-evoked strong Ca(2+) influx via the adenylate cyclase-cAMP-mediated pathway. The OR2AT4 antagonist Phenirat prevented the Sandalore-induced intracellular Ca(2+) increase. Western blot and flow cytometric experiments revealed that stimulation of OR2AT4 reduced the proliferation by decreasing p38-MAPK phosphorylation and induced apoptosis via phosphorylation of p44/42-MAPK. Furthermore, Sandalore increased the number of hemoglobin-containing cells in culture. We described for the first time an OR-mediated pathway in CML and AML that can regulate proliferation, apoptosis and differentiation after activation. This mechanism offers novel therapeutic options for the treatment of AML.
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PMID:Functional characterization of the ectopically expressed olfactory receptor 2AT4 in human myelogenous leukemia. 2755 94

The complement cascade (ComC) cleavage fragments C3a and C5a regulate the trafficking of normal, differentiated hematopoietic cells, although they do not chemoattract more primitive hematopoietic stem/progenitor cells (HSPCs). By contrast, human myeloid and lymphoid leukemia cell lines and clonogenic blasts from chronic myelogenous leukemia (CML) and acute myelogenous leukemia (AML) patients respond to C3 and C5 cleavage fragments by chemotaxis and increased adhesion. Consistent with this finding, C3a and C5a receptors are expressed by leukemic cells at the mRNA (RT-PCR) and protein (FACS) levels, and these cells respond to C3a and C5a stimulation by phosphorylation of p44/42 MAPK and AKT. However, neither of these ComC cleavage fragments have an effect on cell proliferation or survival. In parallel, we found that inducible heme oxygenase 1 (HO-1)-an anti-inflammatory enzyme, is a negative regulator of ComC-mediated trafficking of malignant cells and that stimulation of these cells by C3 or C5 cleavage fragments downregulates HO-1 expression in a p38 MAPK-dependent manner, rendering cells exposed to C3a or C5a more mobile. We propose that, while the ComC is not directly involved in the proliferation of malignant hematopoietic cells, its activation in leukemia/lymphoma patients (e.g., as a result of accompanying infections or sterile inflammation after radio-chemotherapy) enhances the motility of malignant cells and contributes to their dissemination in a p38 MAPK-HO-1 axis-dependent manner. Based on this idea, we propose that inhibition of p38 MAPK or upregulation of HO-1 by available small-molecule modulators would have a beneficial effect on ameliorating expansion and dissemination of leukemia/lymphoma cells in clinical situations in which the ComC becomes activated. Finally, since we detected expression of C3 and C5 mRNA in human leukemic cell lines, further study of the potential role of the complosome in regulating the behavior of these cells is needed.
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PMID:The Complement Cascade as a Mediator of Human Malignant Hematopoietic Cell Trafficking. 3123 94