Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

One of the most serious consequences of cytotoxic cancer therapy is the development of therapy-related acute myeloid leukemia (t-AML), a neoplastic disorder arising from a multipotential hematopoietic stem cell. To gain insights into the molecular basis of this disease, we performed gene expression profiling of CD34(+) hematopoietic progenitor cells from t-AML patients. Our analysis revealed that there are distinct subtypes of t-AML that have a characteristic gene expression pattern. Common to each of the subgroups are gene expression patterns typical of arrested differentiation in early progenitor cells. Leukemias with a -5/del(5q) have a higher expression of genes involved in cell cycle control (CCNA2, CCNE2, CDC2), checkpoints (BUB1), or growth (MYC), and loss of expression of the gene encoding IFN consensus sequence-binding protein (ICSBP). A second subgroup of t-AML is characterized by down-regulation of transcription factors involved in early hematopoiesis (TAL1, GATA1, and EKLF) and overexpression of proteins involved in signaling pathways in myeloid cells (FLT3) and cell survival (BCL2). Establishing the molecular pathways involved in t-AML may facilitate the identification of selectively expressed genes that can be exploited for the development of urgently needed targeted therapies.
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PMID:Expression profiling of CD34+ hematopoietic stem/ progenitor cells reveals distinct subtypes of therapy-related acute myeloid leukemia. 1241 57

Somatic mutation of the FLT3 gene as an internal tandem duplication (ITD) of the juxtamembrane domain-coding sequence causes constitutive tyrosine phosphorylation and activation. Tumor-specific DNA has been documented in the sera of patients with solid tumors even when it is in an early stage. We compared the detection of FLT3 ITD in DNA extracted from cells of bone marrow (BM) aspirations with DNA extracted from peripheral blood (PB) plasma in patients newly diagnosed with acute myeloid leukemia (AML; 85 patients), myelodysplastic syndrome (MDS; 16 patients), and acute lymphocytic leukemia (ALL; 16 patients). FLT3 ITD was detected in 18 (21%) AML samples and in one (6%) MDS sample in both cellular and plasma DNA but in none of the ALL samples. Hemizygous/homozygous FLT3 ITD was detected in five (28%) of the FLT3 ITD-positive AML using plasma DNA, whereas only four of these cases showed hemizygous/homozygous FLT3 ITD using cellular DNA. The presence of FLT3 ITD was associated with significantly shorter survival (P = 0.02) when only patients younger than 50 years of age (48 AML+MDS patients) were considered. This finding was independent of cytogenetics in this age group. However, patients with the FLT3 ITD hemizygous/homozygous phenotype had even shorter survival (P = <0.001). As expected, the presence of FLT3 ITD correlated with higher white blood cell (WBC) counts. These data demonstrate that plasma DNA is a reliable alternative resource for detecting FLT3ITD, especially the hemizygous/homozygous genotype. Furthermore, the data derived from this study support the notion that the presence of FLT3 ITD in conjunction with the absence of the wild-type FLT3 allele predicts an especially poor prognosis for patients with AML.
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PMID:Better detection of FLT3 internal tandem duplication using peripheral blood plasma DNA. 1252 67

Congenital mesoblastic nephroma (CMN) is a rare renal tumor of early infancy with a favorable outcome after complete surgical removal. CMN consists of a heterogeneous group of spindle cell tumors subdivided into "classical", "cellular or atypical" and "mixed" forms based on histologic features. We describe a new case of cellular CMN diagnosed by antenatal ultrasonography with complete remission five years after nephrectomy. Cytogenetic study evidenced a trisomy 11, and real time RT-PCR, but not conventional karyotype, allowed for the detection of the Tel-ETV6/TrkC-NTRK3 fusion transcript as a consequence of a cryptic t(12-15)(p13;q25). As in congenital fibrosarcoma (CFS), two Tel-ETV6/ TrkC-NTRK3 fusion transcripts different by a 42 bp insert in the TrkC kinase domain were expressed. Our observations outline the close links between cellular CMN and CFS. Both tumors have the clinical presentation and histologic features as well as identical cytogenetic and molecular markers in common. Therefore, they are likely to represent the same neoplasm, but occurring at different locations.
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PMID:Cellular mesoblastic nephroma: morphologic, cytogenetic and molecular links with congenital fibrosarcoma. 1265 May 16

Here we report on novel quinoxalines as highly potent and selective inhibitors of the type III receptor tyrosine kinases PDGFR, FLT3, and KIT. These compounds, tricyclic quinoxalines, were generated in order to improve bioavailability over the highly hydrophobic bicyclic quinoxalines. Four of the highly active compounds were characterized in detail and are shown to inhibit PDGFR kinase activity of the isolated receptor as well as in intact cells in the sub-micromolar concentration range. We show that the most active inhibitor (compound 13, AGL 2043) is approximately 15-20 times more potent than its isomer (compound 14, AGL 2044). We therefore compared the three dimensional structures of the two compounds by X-ray crystallography. These compounds are also highly effective in blocking the kinase activity of FLT3, KIT, and the oncogenic protein Tel-PDGFR in intact cells. These compounds are potent inhibitors of the proliferation of pig heart smooth muscle cells. They fully arrest the growth of these cells and the effect is fully reversible. The chemical, biochemical and cellular properties of these compounds as well as the solubility properties make them suitable for development as anti-restenosis and anti-cancer agents.
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PMID:Tricyclic quinoxalines as potent kinase inhibitors of PDGFR kinase, Flt3 and Kit. 1267 Jun 52

Both ITD and D835 mutations of the fms-like tyrosine kinase (FLT3) gene cause constitutive activation of the receptor, in the absence of ligand. We have examined a cohort of 91 patients, AML (80) and MDS (11), to determine the prevalence of these mutations and any correlations between the two mutations and disease prognosis. FLT3/ITD (ITD+) or D835 mutations (D835+) were not detected in MDS patients examined. However, 10% (8/80) and 7.5% (6/80) of AML patients were ITD+ and D835+, respectively. ITD+ patients have a higher rate of relapse than patients with wild-type (WT) FLT3. Median overall survival was 4.6 months (range 0.6-36.2) for ITD+ and 19.85 months (range 0.2-197.5) for WT patients (P=0.0066), and disease-free survival (DFS) was also worse for ITD+ patients than FLT3/WT patients (P=0.047). FLT3/ITD is also a significant prognostic marker for overall survival (OS) and DFS in patients in the standard karyotype group (P=0.0040, 0.0365, respectively). ITD is more prevalent in patients in the standard karyotype category (7/41, 17.1%) as compared to patients in the poor-risk category (1/32, 3.1%). Similar to ITD, D835 mutations were found to be more frequent in patients with standard-risk rather than poor-risk cytogenetic category. WBC count (mean 63.8 x 10(9)/l) was significantly higher in ITD+ patients than patients with D835 mutations (mean 34.8 x 10(9)/l) and WT patients (mean 26.4 x 10(9)/l) (P=0.004). D835 mutants did not appear to have a worse median OS or DFS compared with the WT group. We conclude that FLT3/ITD mutations may be an important prognostic marker in AML, especially in the standard/good risk karyotype groups, where it may allow risk-directed therapy.
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PMID:Prognostic significance of FLT3 ITD and D835 mutations in AML patients. 1269 19

Background. Patients scheduled for myocardial perfusion imaging are often taking several antianginal drugs. There is presently no consensus concerning a regimen of discontinuation before either rest or pharmacologic stress myocardial perfusion imaging. Whether antianginal treatment affects diagnostic sensitivity and specificity is not well documented. Methods and Results. The effect of the three most commonly used antianginal drugs (nitroglycerin, 400 micro g [NTG]; metoprolol, 50 mg [MET]; and amlodipine, 5 mg [AML]) on myocardial perfusion was tested in 49 patients (age, 63 +/- 8 years; 43 men) allocated prospectively to one of the treatments (NTG, n = 25; MET, n = 14; and AML, n = 10). All patients had documented coronary artery disease and were scheduled for elective percutaneous coronary intervention. Patients were studied once on treatment and once off treatment with an interval of 1 to 3 weeks. For NTG, the measurements were performed on the same day with an interval of 1 hour. The MET and AML groups were also studied during dipyridamole-induced hyperemia (0.56 mg. kg(-1). min(-1) for 4 minutes). So that a quantitative value of myocardial perfusion in milliliters per gram per minute could be obtained, myocardial perfusion was quantified with nitrogen 13 ammonia positron emission tomography as an average of the midventricular perfusion in each of the 3 vascular territories. NTG treatment increased the overall resting perfusion (0.75 +/- 0.18 vs 0.86 +/- 0.22, P <.05), whereas resting perfusion was reduced after MET treatment (0.92 +/- 0.14 vs 0.82 +/- 0.17, P <.05). AML treatment did not alter resting perfusion (0.87 +/- 0.22 vs 0.87 +/- 0.23, P = NS). Dipyridamole-induced hyperemia was reduced after treatment with MET (2.02 +/- 0.66 vs l.57 +/- 0.52, P <.001), whereas the hyperemic response was unchanged after treatment with AML (1.54 +/- 0.49 vs 1.86 +/- 0.91, P = NS). Conclusions. Antianginal medication can alter both resting and hyperemic myocardial perfusion and might affect the ability to detect flow-limiting stenosis. NTG increases perfusion, MET reduces perfusion, and AML does not affect perfusion. Larger-scale trials are warranted to establish a consensus for optimal antianginal medication for patients undergoing perfusion imaging.
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PMID:Effect of antianginal medication on resting myocardial perfusion and pharmacologically induced hyperemia. 1273 68

STAT5 phosphorylation has been noted in 69-95% of AML cases by Western blotting. We used flow cytometry to measure phosphorylated STAT5 on a semi-quantitative scale. The method was validated on K562 cells, which constitutively express phosphorylated STAT5, but lose this when BCR-abl tyrosine kinase activity is blocked by STI571. Phosphorylated STAT5 was found to measure 2.22+/-0.09 relative fluorescence units (RFU) falling to 0.925+/-0.005RFU in the presence of STI571. Phosphorylated STAT5 expression was 0.99 to 2.09RFU in 28 primary AML samples. There was no logical cut-off point between positive and negative fluorescence. FLT3 internal tandem duplications, found in 11/28 samples, were not significantly associated with the level of phosphorylated STAT5 expression. We conclude that STAT5 phosphorylation can be measured sensitively by flow cytometry in AML and that its expression should not be dichotomised as present or absent.
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PMID:Flow cytometric measurement of phosphorylated STAT5 in AML: lack of specific association with FLT3 internal tandem duplications. 1280 38

Several studies have shown that mutations in the FLT3 gene are common events in AML, with approximately one third of adult patients harbouring either an internal tandem duplication in the juxtramembrane domain or a D835 mutation in the kinase domain. The majority of studies in pediatric and adult AML have shown that FLT3 mutations are powerful prognostic factors predicting for increased relapse risk and adverse overall survival. Some reports have suggested that loss of the wild type allele might be associated with an even worse prognosis. Changes in the pattern of FLT3 mutations between disease presentation and relapse restrict their value as a marker of minimal residual disease, and have significant implications for therapy. The optimum treatment for patients with FLT3 mutations remains unknown and large prospective studies are warranted to evaluate the efficacy of various treatment modalities such as bone marrow transplantation and targeted therapy with tyrosine kinase inhibitors.
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PMID:Prognostic implications of the presence of FLT3 mutations in patients with acute myeloid leukemia. 1285 87

Our understanding of the genetic basis of acute myeloid leukaemias has been enhanced through cloning of recurring chromosomal translocation breakpoints. However, the remarkable observation, more than a decade ago, that all-trans retinoic acid (ATRA) induced remission in patients with t(15;17) acute promyelocytic leukaemia (APL) was a driving force in the subsequent cloning and characterization of the PML-RARalpha fusion that is causally implicated in the pathogenesis of this disease. Major improvements in treatment and outcome of APL patients have been made since that time by incorporating ATRA in conventional chemotherapy but 30% of APL patients still succumb to complications of their disease or their therapy. Recent information that the haematopoietic receptor tyrosine kinase FLT3 is mutated in about 30% of APL patients suggests strategies for further improving treatment and outcome in this subset of APL patients using small-molecule inhibitors of FLT3. The role of FLT3 mutations in APL and other AML will be discussed.
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PMID:FLT3-activating mutations in acute promyelocytic leukaemia: a rationale for risk-adapted therapy with FLT3 inhibitors. 1293 59

Molecular targeting therapies for hematological malignant diseases such as monoclonal antibodies and small molecules have been reviewed. Imatinib mesylate (STI571) targets the tyrosine kinase activity of the BCR-ABL fusion protein in CML, and was superior to IFN-alpha plus low-dose cytarabine in newly diagnosed chronic-phase CML in a phase III randomized study. Imatinib induced apoptosis in BCR-ABL-positive cells in vitro, and activates several signaling pathways such as PI3K/Akt, STAT5 and Ras/MAPK. Combination therapies with imatinib and new strategies for downregulation of intracellular BCR-ABL protein levels have also been investigated from the phenomenon of resistance to imatinib. Anti-CD20 (rituximab) became the first monoclonal antibody approved for the treatment of a relapsed/refractory follicular/low-grade NHL and promising results were obtained from a phase III randomized study. Although antibody-dependent cell-mediated cytotoxicity and complement-mediated cytotoxicity are likely to be the major effectors of B-cell depletion in vivo, direct cytotoxicity by CD20 monoclonal antibody on B-cell lines in vitro has been reported. Anti-CD33 (Mylotarg) and FLT3 inhibitors for AML have also been used in clinical trials and signaling pathways induced by these agents are under intensive investigation. Arsenic trioxide, like all-TRANS-retinoic acid (ATRA), downregulates promyelocytic leukemia protein/retinoic acid receptor-alpha (PML/RARalpha) fusion protein and induced apoptosis in APL cells, and promising results were obtained from ATRA-resistant APL patients. Finally we show our promising in vitro and in vivo data of R-etodolac (a non-steroidal anti-inflammatory drug lacking cyclooxygenase inhibitor activity) against chronic lymphocytic leukemia (CLL) cells.
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PMID:Apoptosis induced by molecular targeting therapy in hematological malignancies. 1464 49


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