Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ETV6/TEL gene has been reported to fuse to PDGFRbetab MDS1/EVI1, BTL, ACS2, STL, JAK2, ABL, CDX2, TRKC, AML1, and MN1. Among them, PDGFRbeta, ABL, JAK2, and TRKC are tyrosine kinases (TK). We identified a novel ETV6 partner gene, ARG (ABL-related gene or ABL2), another TK gene in a cell line established from a patient with acute myelogenous leukemia (AML-M3) with a t(15;17)(q22;q11.2) and a t(1;12)(q25;p13), which has the remarkable feature to differentiate to mature eosinophils in culture with all-trans retinoic acid and cytokines. The ETV6/ARG transcripts consisted of exon 1 to 5 of ETV6 and the 3' portion of ARG starting from exon 1B or exon 2, resulting in an open reading frame for a fusion protein consisting of the entire PNT oligomerization domain of ETV6 and all of the functional domains of ARG including the TK domain. This is the same protein structure as identified in the other ETV6 TK fusion proteins. The reciprocal ARG/ETV6 transcript was not expressed, and the normal ETV6 allele was not deleted or rearranged. Although the ABL is known to be involved in various human malignancies, ARG has not been involved in human malignancies despite its high homology to ABL. Thus, this is the first report showing involvement of ARG in human leukemia. The ETV6/ARG protein may be involved in the unique differentiation capacity of this cell line. (Blood. 2000;95:2126-2131)
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PMID:A new ETV6/TEL partner gene, ARG (ABL-related gene or ABL2), identified in an AML-M3 cell line with a t(1;12)(q25;p13) translocation. 1070 84

A G-->T transversion at nucleotide 2467 of the c-KIT gene leading to Asp816-->Tyr (D816Y) substitution in the phosphotransferase domain has been previously identified in a patient with rapidly progressing AML-M2 and mast cell involvement; the patient's blasts had a 47,XY, +4,t(8;21)(q22;q22) karyotype. Herein we confirm the simultaneous presence of both major chromosomal changes by multicolor fluorescence in situ hybridization (FISH) on interphase CD34+ mononuclear cells. By setting up culture leukemic blasts, spontaneous differentiation of adherent cells with mast-cell like features was proved by histochemical and immunoenzymatic analyses. Fluorescence in situ hybridization evidence of trisomy 4 confirmed the origin of differentiated cells from the leukemic blasts. Semiquantitative polymerase chain reaction (PCR) and phosphoimage densitometry of wild-type and mutated KIT alleles on bone marrow blasts made it possible to demonstrate that chromosome 4 trisomy led to a double dosage of the mutated KIT allele. This finding, and that of trisomy 7 and MET mutation in hereditary renal carcinoma represent the only cases of human tumors in which an increased number of chromosomes carrying an oncogene activated by point mutation have been detected.
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PMID:Trisomy 4 leading to duplication of a mutated KIT allele in acute myeloid leukemia with mast cell involvement. 1081 67

Several tyrosine kinase oncogenes have been associated with myeloproliferative diseases, including Bcr/Abl, Tel/Abl, Tel/Jak2, and Tel/PDGFR. One target molecule shared by these oncogenes is known to be STAT5. We generated sublines of Ba/F3 cells in which either wild-type STAT5 or a constitutively active mutant of STAT5 (STAT5-1*6) were expressed under the control of a tetracycline-inducible promoter. These cell lines were compared with a Ba/F3 cell line in which the expression of p210(Bcr/Abl) was made inducible by a similar promoter. Before induction, all cells were dependent on interleukin 3 (IL-3) for growth and survival. Both STAT5-1*6 and Bcr/Abl enhanced viability and induced proliferation in the absence of IL-3. We found that the proviability protein Bcl-X(L), but not Bcl-2, was induced by both p210(Bcr/Abl) and STAT5-1*6. Using a Bcl-X gene promoter construct fused to a luciferase complementary DNA (cDNA), both p210(Bcr/Abl) and STAT5-1*6 were shown to induce transcription of Bcl-X. The increase in transcription of the Bcl-X promoter and the increase in Bcl-X protein, due to p210(Bcr/Abl), were blocked by expression of a dominant negative STAT5 mutant. Interestingly, however, STAT5-1*6 required the continued presence of IL-3 to cause a significant increase in Bcl-X(L) protein, whereas p210(Bcr/Abl) did not need IL-3. Studies with enzyme inhibitors suggest that the extra signal supplied by IL-3 may be supplied by the PI3K pathway. Overall, these data suggest that constitutively activated STAT5 can increase viability and proliferation of Ba/F3 cells. This may contribute to, but is not likely sufficient for, the enhanced viability associated with Bcr/Abl transformation.
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PMID:Bcr/Abl activates transcription of the Bcl-X gene through STAT5. 1097 76

Aberrant expression of FLT3 has been found in most cases of B-lineage ALL and AML, and subsets of T cell ALL, CML in blast crisis and CLL. In 20% of patients with AML the receptor has small internal tandem duplications of the juxtamembrane region which appear to contitutively activate the receptor. To investigate whether FLT3 activation could play a role in leukemia, we generated a constitutively activated FLT3 by fusing its cytoplasmic domain to the helix-loop-helix domain of TEL in analogy to the fusion that occurs with TEL-PDGFR in CMML. In vitro translation assays demonstrated oligomerization and intrinsic tyrosine kinase activity of the TEL-FLT3 chimeric receptor. Constitutively activated TEL-FLT3 conferred IL-3 independence and long-term proliferation to transfected Ba/F3 cells. Immunoblot analyses showed that JAK 2, STAT 3, STAT 5a, STAT 5b and CBL were tyrosine-phosphorylated in TEL-FLT3 expressing Ba/F3 cells in the absence of IL-3. These data suggest a possible role for the JAK/STAT pathway in FLT3 signaling. Transplantation of TEL-FLT3 expressing Ba/F3 cells into syngeneic mice caused mortality in all mice by 3 weeks after injection. Histopathologic analysis demonstrated a massive infiltration of mononuclear cells in the liver, spleen and bone marrow. The mimicking of naturally occurring TEL fusions provides an approach to assess aspects of the biology of activated FLT3, or other receptor-type tyrosine kinases (RTKs) in leukemic transformation.
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PMID:Constitutive activation of FLT3 stimulates multiple intracellular signal transducers and results in transformation. 1102 52

In this study, we examined the involvement of the phosphatidylinositol 3-kinase (PI3-K) and p70S6 kinase signal transduction pathway in the interleukin-1(IL-1)-mediated proliferation and cytokine production by normal and leukemic myeloid cells. Total AML blast populations, early progenitor (CD34(+)/CD36(-)) cells, and more differentiated (CD34(-)/CD36(+)) cells were treated with the PI3-K inhibitor Ly294002 and p70S6K inhibitor rapamycin. The effects on proliferation, IL-6 protein secretion, and intracellular signaling cascades were determined and compared with normal CD34(+) cells and monocytes. The function of the PI3-K pathway was dependent on the differentiation state of the AML cell population. In immature blasts, the IL-1-induced proliferation was strongly inhibited by Ly294002 and rapamycin, without a distinct effect on IL-6 protein production. In contrast, in mature monocytic blast cells inhibition of the PI3-K signaling route had a stimulatory effect on IL-6 protein secretion. Interestingly, these findings were not specifically linked to the malignant counterpart but were also observed with normal CD34(+) sorted cells vs mature monocytes. Evidence is provided that the Ly294002-induced increase in IL-6 protein secretion is linked to the cAMP dependent signaling pathway and not to changes in the phosphorylation of ERK or p38. However, although the enhanced IL-6 protein secretion is cAMP dependent, it was not found to be mediated by protein kinase A (PKA) or by the GTP-ase Rap1. This study indicates that inhibition of the PI3-K signaling pathway has an inhibitory effect on cell proliferation but a stimulatory effect on IL-6 expression mediated by a cAMP-dependent but PKA-independent route.
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PMID:An inhibitor of PI3-K differentially affects proliferation and IL-6 protein secretion in normal and leukemic myeloid cells depending on the stage of differentiation. 1106 72

It has been proposed that adoptive immunotherapy, for the treatment of relapsed AML, with cytotoxic T lymphocytes which show a relative specificity for the leukemic cells may have the advantage of maximizing the beneficial anti-leukemic effect whilst minimizing the probability of graft-versus-host disease. In this study we differentiated peripheral blood AML cells in vitro into functional dendritic cells (DCs), as demonstrated by cell morphology, immunophenotype and functional activity, in the presence of GM-CSF, IL-4, TNF-alpha and FLT3 ligand. Such DCs could be differentiated from 77% of AML patients, irrespective of their FAB classification and clinical status and, in all cases tested, the DCs were shown to derive from the leukemic clone by FISH analysis. Importantly, from >60% of AML patients, autologous T lymphocytes stimulated with these in vitro generated leukemic DCs displayed specific cytotoxic activity against AML blasts but low reactivity against autologous non-leukemic targets and HLA-matched normal PBMNCs therefore suggesting that the CTLs were AML-specific. The use of FLT3 ligand in our system resulted in a significantly higher number of leukemic DCs as compared to cultures from which FLT3 ligand was omitted which is obviously advantageous if large numbers of specific CTLs are to be generated in the shortest possible time.
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PMID:Leukemic dendritic cells generated in the presence of FLT3 ligand have the capacity to stimulate an autologous leukemia-specific cytotoxic T cell response from patients with acute myeloid leukemia. 1123 40

The tyrosine kinase inhibitor STI571 inhibits BCR/ABL and induces hematologic remission in most patients with chronic myeloid leukemia. In addition to BCR/ABL, STI571 also inhibits v-Abl, TEL/ABL, the native platelet-derived growth factor (PDGF)beta receptor, and c-KIT, but it does not inhibit SRC family kinases, c-FMS, FLT3, the epidermal growth factor receptor, or multiple other tyrosine kinases. ARG is a widely expressed tyrosine kinase that shares substantial sequence identity with c-ABL in the kinase domain and cooperates with ABL to regulate neurulation in the developing mouse embryo. As described here, ARG has recently been implicated in the pathogenesis of leukemia as a fusion partner of TEL. A TEL/ARG fusion was constructed to determine whether ARG can be inhibited by STI571. When expressed in the factor-dependent murine hematopoietic cell line Ba/F3, the TEL/ARG protein was heavily phosphorylated on tyrosine, increased tyrosine phosphorylation of multiple cellular proteins, and induced factor-independent proliferation. The effects of STI571 on Ba/F3 cells transformed with BCR/ABL, TEL/ABL, TEL/PDGFbetaR, or TEL/ARG were then compared. STI571 inhibited tyrosine phosphorylation and cell growth of Ba/F3 cells expressing BCR/ABL, TEL/ABL, TEL/PDGFbetaR, and TEL/ARG with an IC(50) of approximately 0.5 microM in each case, but it had no effect on untransformed Ba/F3 cells growing in IL-3 or on Ba/F3 cells transformed by TEL/JAK2. Culture of TEL/ARG-transfected Ba/F3 cells with IL-3 completely prevented STI571-induced apoptosis in these cells, similar to what has been observed with BCR/ABL- or TEL/ABL-transformed cells. These results indicate that ARG is a target of the small molecule, tyrosine kinase inhibitor STI571.
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PMID:ARG tyrosine kinase activity is inhibited by STI571. 1129 Jun 9

The Ets family contains a growing number of transcriptional activators and inhibitors, which activity is regulated by phosphorylation and protein-protein interactions. Among these factors, Ets1, Erg1 and Fli1 are expressed in endothelial cells during angiogenesis in normal and pathological development. The expression of these transcription factors is regulated by angiogenic factors in cultured endothelial cells, as well as by various stresses occurring during angiogenesis. Transfection experiments and transgenic mice analysis revealed that Ets family members are involved in the transcriptional regulation of endothelial specific genes such as those encoding Tie1 and -2, VEGFR1 and -2 and VE-Cadherin. In vitro studies plead for a role of Ets family members in endothelial cell adhesion, spreading and motility. Gene inactivation experiments show that Ets1 is dispensable for embryonic development. The phenotype of knocked-out embryos indicates that Tel is required for maintenance of the developing vascular network in the yolk sac. Altogether, we suggest that Ets family members act both positively and negatively during the different steps of the angiogenic process. The regulation of the initiation of gene transcription arises from the combined activity of different transcriptional regulators. Therefore very few transcription factors are specific for a physiological process, or a given cell type. The transcriptional network that regulates blood vessel formation involves transcription factors which are expressed in a variety of situations. The Lung Kruppel Like Factor (LKLF) which is required for blood vessel stabilisation during murine development is also expressed in the primitive vertebrae and in the lung of the adult (C.T. Kuo, M.L. Veselits, K.P. Barton, M.M. Lu, C. Clendenin, J.M. Leiden, The LKLF transcription factor is required for normal tunica media formation and blood vessel stabilisation during murine embryogenesis, Genes Dev. 11 (22) (1997) 2996-3006). Scl/Tal1 which is essential for angiogenic remodelling of the yolk sac capillary network (J.E. Visvader, Y. Fujiwara, S.H. Orkin, Unsuspected role for the T-cell leukemia protein SCL/tal-1 in vascular development, Genes Dev. 12 (4) (1998) 473-479), is involved in blood cell development and is also expressed in the developing brain. The EPAS transcription factor which was thought to be endothelial cell specific in the mouse embryo (H. Tian, S.L. McKnight, D.W. Russell, Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells, Genes Dev. 11 (1) (1997) 72-82) is also expressed in the liver, kidney and cells of the sympathetic nervous system of the chick embryo (J. Favier, H. Kempf, P. Corvol, J.M. Gasc, Cloning and expression pattern of EPAS1 in the chicken embryo. Colocalization with tyrosine hydroxylase, FEBS Lett. 462 (1-2) (1999) 19-24). Ets1, which expression was originally detected in lymphoid cells of adult tissues, has been the first transcription factor to be identified in endothelial cells during angiogenesis in the embryo (B. Vandenbunder, L. Pardanaud, T. Jaffredo, M.A. Mirabel, D. Stehelin, Complementary patterns of expression of c-etsl, c-myb and c-myc in the blood-forming system of the chick embryo, Development 107 (1989) 265-274 [5]) and in tumours (N. Wernert, M.B. Raes, P. Lassalle, M.P. Dehouck, B. Gosselin, B. Vandenbunder, D. Stehelin, The c-ets 1 proto-oncogene is a transcription factor expressed in endothelial cells during tumor vascularisation and other forms of angiogenesis in man, Am. J. Path. 140 (1992) 119-127 [6]). Since then, the Ets family has extended and this review will emphasise the relationships between these factors and angiogenesis.
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PMID:The Ets family contains transcriptional activators and repressors involved in angiogenesis. 1131 8

FLT3 is a member of the type III receptor tyrosine kinase (RTK) family. These receptors all contain an intrinsic tyrosine kinase domain that is critical to signaling. Aberrant expression of the FLT3 gene has been documented in both adult and childhood leukemias including AML, ALL and CML. In addition, 17-27% of pediatric and adult patients with AML have small internal tandem duplication mutations in FLT3. Patients expressing the mutant form of the receptor have been shown to have a decreased chance for cure. Our previous study, using a constitutively activated FLT3, demonstrated transformation of Ba/F3 cells and leukemic development in an animal model. Thus, there is accumulating evidence for a role for FLT3 in human leukemias. This has prompted us to search for inhibitors of FLT3 as a possible therapeutic approach in these patients. AG1296 is a compound of the tyrphostin class that is known to selectively inhibit the tyrosine kinase activity of the PDGF and KIT receptors. Since FLT3 is a close relative of KIT, we wanted to test the possible inhibitory activity of AG1296 on FLT3. In transfected Ba/F3 cells, AG1296 selectively and potently inhibited autophosphorylation of FL-stimulated wild-type and constitutively activated FLT3. Treatment by AG1296 abolished IL-3-independent proliferation of Ba/F3 cells expressing the constitutively activated FLT3 and thus, reversed the transformation mediated by activated FLT3. Inhibition of FLT3 activity by AG1296 in cells transformed by activated FLT3 resulted in apoptotic cell death, with no deleterious effect on their parental counterparts. Addition of IL-3 rescued the growth of cells expressing activated FLT3 in the presence of AG1296. This demonstrates that the inhibition is specific to the FLT3 pathway in that it leaves the kinases of the IL-3 pathway and other kinases further downstream involved in proliferation intact. Several proteins phosphorylated by the activated FLT3 signaling pathway, including STAT 5A, STAT 5B and CBL, were no longer phosphorylated when these cells were treated with AG1296. The activity against FLT3 suggests a potential therapeutic application for AG1296 or similar drugs in the treatment of leukemias involving deregulated FLT3 tyrosine kinase activity and as a tool for studying the biology of FLT3.
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PMID:Inhibition of FLT3-mediated transformation by use of a tyrosine kinase inhibitor. 1145 67

Myelodysplastic syndrome (MDS) is characterised by ineffective erythropoiesis and poor progenitor response to erythropoietin (Epo). The aim of this study was to determine the role of the Epo-R mediated signalling in the rise of MDS and whether alteration of signalling pathways contribute to the leukeamogenesis from MDS to acute leukaemia. We analysed Epo and GM-CSF induced ERK1/2 activation, c-Fos expression, STAT-5 and AP-1 DNA binding activities in mononuclear cells of umbilical cord blood (UCBMNC), normal marrow (NBMMNC) or marrow with MDS, AML with prior MDS and de novo AML. In UCBMNC and NBMMNC, Epo and GM-CSF induced the activation of STAT-5 DNA binding and ERK 1/2 activation (n = 6). In contrast, in MDS RA, both signalling pathways were activated only by GM-CSF but not by Epo (n = 7). In acute leukaemia, elevated basal activity of STAT-5 DNA binding appeared in 8/8 cases, which was independent of Epo or GM-CSF treatment. In normal and MDS samples, c-Fos and Egr-1 proteins were not detectable and the expression levels were not increased by Epo or GM-CSF treatment. In contrast, we found an elevated level of c-Fos expression in 5/8 acute leukemia cases, which was not further increased in the presence of Epo or GM-CSF. The elevated c-Fos expression was accompanied by an extremely high blast number in 5/5 cases. These results suggest that impaired ERK/MAPK activation, similarly to impaired STAT-5 activation in Epo-R signalling, may be responsible for the apoptotic process and the block of maturation in MDS RA. The results also suggest that the appearance of the constitutively activated STAT-5 DNA binding and c-Fos expression may be used as a predictor of the blastic transformation.
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PMID:Unregulated activation of STAT-5, ERK1/2 and c-Fos may contribute to the phenotypic transformation from myelodysplastic syndrome to acute leukaemia. 1158 24


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