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

---

Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The objective of this study was to explore the differences between refractory anemia with ringed sideroblast (RARS) and RARS associated with marked thrombocytosis (RARS-T) in the clinical, biological features and prognosis. The morphological changes of cells were observed by bone marrow smear and biopsy. Immunologic phenotype was analyzed by flow cytometry, and chromosome was examined by conventional chromosomal analysis. JAK2 V617F and MPL W515L mutations were screened by allele-specific polymerase chain reaction (AS-PCR) and sequence analysis. The results showed that this case was clinically diagnosed as RARS with thrombophilia, the level of serum potassium was positively related with platelet counts. When platelets increased, the clusters of atypical giant platelets and megakaryocytes were observed in peripheral blood and bone marrow examined by bone marrow smear and bone marrow biopsy respectively, JAK2 V617F and MPL W515L mutations were negative. It is concluded that RARS may transform into RARS-T accompanied with megakaryocyte proliferation, large atypical platelets and negative JAK2 V617F. Preventing thrombophilia and monitoring relative gene mutations are necessary when atypical giant platelets and fluctuant platelet counts occurred in process of RARS with tendency to RARS-T.
...
PMID:[Clinical and biological features in refractory anemia with ringed sideroblasts with fluctuant platelet counts]. 2072 24

JAK2 V617F and MPL W515L/K mutations have been reported in approximately 50% and 5% of the patients with essential thrombocythemia (ET), respectively. We investigated the frequency of MPL W515L/K mutations in a series of consecutive patients with ET and post-essential thrombocythemia myelofibrosis (post-ET MF). The study subjects were 63 patients diagnosed either with ET (N=59) or post-ET MF (N=4) at our institution between June 2006 and February 2010. Among them, 35 (55.6%) had the JAK2 V617F mutation. MPL W515L/K mutations were detected by direct sequencing analyses of exon 10, and 2 patients were found to harbor the following MPL mutations: W515L in 1 patient with ET and W515K in 1 patient with post-ET MF. Neither of the patients had the JAK2 V617F mutation. Thus, the frequency of MPL W515L/K mutation in Korean patients with ET/post-ETMF was 3.2% (2/63) and that in JAK2 V617F-negative ET/post-ET MF was 7.1% (2/28) [corrected]. This is the first study to report the frequency of JAK2 V617F and MPL W515L/K mutations in Korean patients with ET/post-ET MF.
...
PMID:JAK2 V617F and MPL W515L/K mutations in Korean patients with essential thrombocythemia. 2089 78

The Philadelphia chromosome-negative chronic myeloproliferative neoplasms (MPNs) have recently been the focus of tremendous advances in basic knowledge of disease pathophysiology following the recognition of mutations in JAK2 and MPL. These discoveries also led to refinement of the criteria employed for diagnosis. The prognostic roles of the JAK2 V617F mutation and of leukocytosis as independent risk factors for thrombosis, which represents the leading cause of death in patients with polycythemia vera and essential thrombocythemia, are supported by retrospective studies. A new risk stratification approach to the patient with primary myelofibrosis allows clinicians to distinguish categories of patients with significantly different expected survival. Finally, new drugs are currently being tested for MPNs, and molecular discoveries could ultimately lead to the development of a specific targeted therapy. Overall, significant advances in diagnosis, prognostication, and treatment have taken place in the last couple of years in the field of MPNs.
...
PMID:Recent advances in diagnosis and treatment of chronic myeloproliferative neoplasms. 2094 70

Clonal hematopoiesis triggered by somatic mutations plays a central role in the pathogenesis of Philadelphia chromosome negative chronic myeloproliferative neoplasms (MPNs). After the discovery of JAK and MPL mutations, continual technological advances have led to the identification of increasing numbers of genetic defects in MPN patients, most of them chromosomal aberrations such as deletions and acquired uniparental disomies. Although efforts to map the genetic lesions to single genes resulted in the discovery of defects in the TET2 and CBL genes, most of the target genes comprised in the chromosomal lesions still remain to be identified. In this review, the different genetic defects found in MPN and their relationships to each other and to disease pathogenesis are critically evaluated. At present, most of the evidence points to a random acquisition of phenotypic and non phenotypic mutations contributing to clonal heterogeneity in MPN. The origin of genetic instability in context of hereditary factors and the common JAK2 haplotype predisposing for the disease are discussed. Furthermore, we address how the choice of therapeutic approaches could be influenced by the genetic complexity.
...
PMID:Molecular pathogenesis of Philadelphia chromosome negative chronic myeloproliferative neoplasms. 2106 46

It is currently assumed that myelofibrosis (MF) originates from acquired mutations that target the hematopoietic stem cell and induce dysregulation of kinase signaling, clonal myeloproliferation, and abnormal cytokine expression. These pathogenetic processes are interdependent and also individually contributory to disease phenotype-bone marrow stromal changes, extramedullary hematopoiesis, ineffective erythropoiesis, and constitutional symptoms. Molecular pathogenesis of MF is poorly understood despite a growing list of resident somatic mutations that are either functionally linked to Janus kinase (JAK)-signal transducer and activator of transcription hyperactivation (eg JAK2, MPL, and LNK mutations) or possibly involved in epigenetic dysregulation of transcription (TET2, ASXL1, or EZH2 mutations). Current prognostication in primary MF is based on the Dynamic International Prognostic Scoring System-plus model, which uses 8 independent predictors of inferior survival to classify patients into low, intermediate 1, intermediate 2, and high-risk disease groups; corresponding median survivals are estimated at 15.4, 6.5, 2.9, and 1.3 years. Such information is used to plan a risk-adapted treatment strategy for the individual patient, which might include observation alone, conventional or investigational (eg, JAK inhibitors, pomalidomide) drug therapy, allogenic stem cell transplantation with reduced- or conventional-intensity conditioning, splenectomy, or radiotherapy. I discuss these treatment approaches in the context of who should get what and when.
...
PMID:How I treat myelofibrosis. 2171 7

In this study we investigated whether neoplastic transformation occurring in Philadelphia (Ph)-negative myeloproliferative neoplasms (MPNs) could involve also the endothelial cell compartment. We evaluated the level of endothelial colony-forming cells (E-CFCs) in 42 patients (15 with polycythemia vera, 12 with essential thrombocythemia, and 15 with primary myelofibrosis). All patients had 1 molecular abnormality (JAK2(V617F) or MPL(W515K) mutations, SOCS gene hypermethylation, clonal pattern of growth) detectable in their granulocytes. The growth of colonies was obtained in 22 patients and, among them, patients with primary myelofibrosis exhibited the highest level of E-CFCs. We found that E-CFCs exhibited no molecular abnormalities in12 patients, had SOCS gene hypermethylation, were polyclonal at human androgen receptor analysis in 5 patients, and resulted in JAK2(V617F) mutated and clonal in 5 additional patients, all experiencing thrombotic complications. On the whole, patients with altered E-CFCs required antiproliferative therapy more frequently than patients with normal E-CFCs. Moreover JAK2(V617F)-positive E-CFCs showed signal transducer and activator of transcription 5 and 3 phosphorylation rates higher than E-CFCs isolated from healthy persons and patients with MPN without molecular abnormalities. Finally, JAK2(V617F)-positive E-CFCs exhibited a high proficiency to adhere to normal mononuclear cells. This study highlights a novel mechanism underlying the thrombophilia observed in MPN.
...
PMID:Endothelial progenitor cells are clonal and exhibit the JAK2(V617F) mutation in a subset of thrombotic patients with Ph-negative myeloproliferative neoplasms. 2121 85

To update oncologists on pathogenesis, contemporary diagnosis, risk stratification, and treatment strategies in BCR-ABL1-negative myeloproliferative neoplasms, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Recent literature was reviewed and interpreted in the context of the authors' own experience and expertise. Pathogenetic mechanisms in PV, ET, and PMF include stem cell-derived clonal myeloproliferation and secondary stromal changes in the bone marrow and spleen. Most patients carry an activating JAK2 or MPL mutation and a smaller subset also harbors LNK, CBL, TET2, ASXL1, IDH, IKZF1, or EZH2 mutations; the precise pathogenetic contribution of these mutations is under investigation. JAK2 mutation analysis is now a formal component of diagnostic criteria for PV, ET, and PMF, but its prognostic utility is limited. Life expectancy in the majority of patients with PV or ET is near-normal and disease complications are effectively (and safely) managed by treatment with low-dose aspirin, phlebotomy, or hydroxyurea. In PMF, survival and quality of life are significantly worse and current therapy is inadequate. In ET and PV, controlled studies are needed to show added value and justify the risk of unknown long-term health effects associated with nonconventional therapeutic approaches (eg, interferon-alfa). The unmet need for treatment in PMF dictates a different approach for assessing the therapeutic value of new drugs (eg, JAK inhibitors, pomalidomide) or allogeneic stem-cell transplantation.
...
PMID:Myeloproliferative neoplasms: molecular pathophysiology, essential clinical understanding, and treatment strategies. 2157 37

Somatic mutations of MPL exon 10, mainly involving a W515 substitution, have been described in JAK2 (V617F)-negative patients with essential thrombocythemia and primary myelofibrosis. We used direct sequencing and high-resolution melt analysis to identify mutations of MPL exon 10 in 570 patients with myeloproliferative neoplasms, and allele specific PCR and deep sequencing to further characterize a subset of mutated patients. Somatic mutations were detected in 33 of 221 patients (15%) with JAK2 (V617F)-negative essential thrombocythemia or primary myelofibrosis. Only one patient with essential thrombocythemia carried both JAK2 (V617F) and MPL (W515L). High-resolution melt analysis identified abnormal patterns in all the MPL mutated cases, while direct sequencing did not detect the mutant MPL in one fifth of them. In 3 cases carrying double MPL mutations, deep sequencing analysis showed identical load and location in cis of the paired lesions, indicating their simultaneous occurrence on the same chromosome.
...
PMID:Deep sequencing reveals double mutations in cis of MPL exon 10 in myeloproliferative neoplasms. 2122 32

The seminal discovery of the JAK2V617F mutation, which is highly prevalent in Philadelphia-negative myeloproliferative disorders, now renamed neoplasms, triggered an almost unprecedented explosion of interest and data in the field. Descriptions of additional mutations in exon 12 of JAK2, at position 515 in MPL, and a number of other mutations at low frequency followed these discoveries. These advances in our understanding of molecular pathogenesis of these conditions coincided with the publication of results from two major clinical studies, ECLAP and PT-1, which contributed important clinical insights and facilitated significant correlative data collection. This article, focusing mainly upon essential thrombocythemia and polycythemia vera, reviews four major themes: the impact upon classification of these disorders considering a radical review of current terminology, and then three areas pertinent to clinical management: the indications for cytoreductive therapy in which the key targets are to reduce thrombohemorrhagic complications, relieve disease-related symptoms, and minimize the risk of transformation to secondary myeloid malignancy such as myelodysplasia, leukemia, and secondary myelofibrosis; and second reviewing current and, last, future therapeutic options, in particular interferon and JAK2 inhibitors.
...
PMID:Rethinking disease definitions and therapeutic strategies in essential thrombocythemia and polycythemia vera. 2123 82

Mutations in the thrombopoietin receptor gene (myeloproliferative leukemia, MPL) have been reported in patients with JAK2 V617F-negative chronic myeloproliferative disorders (MPDs). We evaluated the prevalence of MPL mutations relative to JAK2 mutations in patients with suspected MPDs. A total of 2790 patient samples submitted for JAK2 mutation analysis were tested using real-time polymerase chain reaction and bidirectional sequencing of plasma RNA. JAK2 V617F-negative samples were tested for JAK2 exons 12 to 14 mutations, and those with negative results were then tested for mutations in MPL exons 10 and 11. Of the 2790 patients, 529 (18.96%) had V617F, 12 (0.43%) had small insertions or deletions in exon 12, and 7 (0.25%) had other JAK2 mutations in exons 12 to 14. Of the 2242 JAK2 mutation-negative patients, 68 (3.03%) had MPL mutations. W515L was the predominant MPL mutation (n=46; 68%), and 10 (15%) patients had other W515 variants. The remaining MPL mutations (n=12, 17%) were detected at other locations in exons 10 and 11 and included 3 insertion/deletion mutations. The S505N mutation, associated with familial MPD, was detected in 3 patients. Overall, for every 100 V617F mutations in patients with suspected MPDs, there were 12.9 MPL mutations, 2.3 JAK2 exon 12 mutations, and 1.3 JAK2 exons 13 to 14 mutations. These findings suggest that MPL mutation screening should be performed before JAK2 exons 12 to 14 testing in JAK2 V617F-negative patients with suspected MPDs.
...
PMID:MPL mutation profile in JAK2 mutation-negative patients with myeloproliferative disorders. 2132 37


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---