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 discovery this year of a single mutation in the Janus Kinase (JAK)-2 gene in a high percentage of cases of polycythaemia vera (PV), essential thrombocythaemia (ET) and myelofibrosis suggests that it maybe the underlying molecular mechanism for these disorders. Different approaches from the inhibition of the tyrosine kinase JAK2, widespread search for mutations in tyrosine kinases, and investigation of the short arm of chromosome 9 where JAK2 is located all led to the discovery of the V617F JAK2 mutation. Substitution of a valine for a phenylalanine destabilizes the JH2 domain of JAK2 causes loss of the auto-inhibitory activity of this domain and explains some of the biological phenomena observed in patients with myeloproliferative disorders (MPD). The V617F JAK2 mutation can be detected by PCR-direct sequencing using DNA from the granulocyte lineage or with increased sensitivity by the amplification refractory mutation system using DNA from unfractionated blood. Pyrosequencing assays can be used to quantitate allele ratios to accurately define homozygote and heterozygote status. This single mutation is widespread having been detected in related MPD and other haematological malignancies. This leads to a number of further questions about the role of this single mutation in the clinical pattern of disease.
...
PMID:The V617F JAK2 mutation and the myeloproliferative disorders. 1628 6

The primary disease process in myelofibrosis with myeloid metaplasia (MMM) is clonal myeloproliferation with varying degrees of phenotypic differentiation. This is characteristically accompanied by secondary intramedullary collagen fibrosis, osteosclerosis, angiogenesis, and extramedullary hematopoiesis. Modern clonality studies have confirmed the multipotent stem-cell origin of the neoplastic process in MMM. The nature of the specific oncogenic mutation(s) is currently being unraveled with the recent discovery of an association between a somatic point mutation of JAK2 tyrosine kinase (V617F) and bcr/abl-negative myeloproliferative disorders, including MMM. The pathogenetic mechanisms that underlie the secondary bone marrow stromal changes in MMM are also incompletely understood. Mouse models of this latter disease aspect have been constructed by either in vivo overexpression of thrombopoietin (TPOhigh mice) or megakaryocyte lineage restricted underexpression of the transcription factor GATA-1 (GATA-1low mice). Gene knockout experiments using such animal models have suggested the essential role of hematopoietic cell-derived transforming growth factor beta1 in inducing bone marrow fibrosis and stromal cell-derived osteoprotegerin in promoting osteosclerosis. However, experimental myelofibrosis in mice does not recapitulate clonal myeloproliferation that is fundamental to human MMM. Other cytokines that are implicated in mediating myelofibrosis and angiogenesis in MMM include basic fibroblast, platelet-derived, and vascular endothelial growth factors. It is currently assumed that such cytokines are abnormally released from clonal megakaryocytes as a result of a pathologic interaction with neutrophils (eg, emperipolesis). This latter phenomenon, through neutrophil-derived elastase, could also underlie the abnormal peripheral-blood egress of myeloid progenitors in MMM.
...
PMID:Pathogenesis of myelofibrosis with myeloid metaplasia. 1629 80

Myeloproliferative disorders (MPDs) are heterogeneous diseases that occur at the level of a multipotent hematopoietic stem cell. They are characterized by increased blood cell production related to cytokine hypersensitivity and virtually normal cell maturation. The molecular pathogenesis of the MPDs has been poorly understood, except for chronic myeloid leukemia (CML), where the Bcr-Abl fusion protein exhibits constitutive kinase activity. Since some rare MPDs are also related to a dysregulated kinase activity, a similar mechanism was thought to be likely responsible for the more frequent MPDs. We investigated the mechanisms of endogenous erythroid colony formation (EEC) by polycythemia vera (PV) erythroid progenitor cells and found that EEC formation was abolished by a pharmacological inhibitor of JAK2 as well as an siRNA against JAK2. JAK2 sequencing revealed a unique mutation in the JH2 domain leading to a V617F substitution in more than 80% of the PV samples. This mutation in the pseudokinase autoinhibitory domain results in constitutive kinase activity and induces cytokine hypersensitivity or independence of factor-dependent cell lines. Retroviral transduction of the mutant JAK2 into murine HSC leads to the development of an MPD with polycythemia. The same mutation was found in about 50% of patients with idiopathic myelofibrosis (IMF) and 30% of patients with essential thrombocythemia (ET). Using different approaches, four other teams have obtained similar results. The identification of the JAK2 mutation represents a major advance in our understanding of the molecular pathogenesis of MPDs that will likely permit a new classification of these diseases and the development of novel therapeutic approaches.
...
PMID:A unique activating mutation in JAK2 (V617F) is at the origin of polycythemia vera and allows a new classification of myeloproliferative diseases. 1630 80

The optimal management of patients with polycythemia vera (PV) and essential thrombocythemia (ET) continues to be controversial. Both diseases present diagnostic challenges and there is a paucity of data from randomized clinical trials to guide therapeutic decisions. However, the past two years have seen major advances in our understanding of these myeloproliferative disorders (MPD). First, the ECLAP study demonstrated the anti-thrombotic efficacy of aspirin in patients with PV. Second, the PT-1 trial, the largest randomized study of any MPD, has provided much needed guidance on the optimal management of patients with ET. Third, the identification of a single JAK2 mutation in most patients with PV, and in some of those with ET, illuminates the pathogenesis of these diseases and raises questions about the boundary between them. For the purpose of management decisions, it remains appropriate to consider them as separate entities for the time being. However, as we learn more about the clinical significance of the JAK2 mutation, it seems likely that the coming years will see major changes in the way we classify and manage these disorders.
...
PMID:Management of polycythemia vera and essential thrombocythemia. 1630 81

The myeloproliferative disorders have been the "poor cousins" in the family of hematological malignancies for some time. Recently this field has advanced considerably with the description of a mutation in the JAK2 kinase detectable in the majority of patients and the publication of two landmark clinical trials--ECLAP and MRC PT1. But although both ECLAP and MRC PT1 inform clinical management and allude to the complexities of thrombosis we still lack fundamental knowledge, and our understanding of thrombosis in these conditions has not paralleled advances in the field of thrombosis and vascular biology. The predominant clinical complications of essential thrombocythemia and polycythemia vera are thrombotic and hemorrhagic; these significantly impact upon prognosis and quality of life. Here the current status of our knowledge is reviewed with specific emphasis upon the role of the platelet in the pathogenesis of thrombosis as well as the impact of recent data from ECLAP and MRC PT1.
...
PMID:Platelets and thrombosis in myeloproliferative diseases. 1630 12

Protein kinases have emerged as one of the most promising targets for rational drug discovery. In a similar manner to imatinib mesylate (Gleevec), hematological malignancies offer multiple pharmacologic opportunities for manipulation of kinase-induced tumor cell proliferation. Certain kinases have been validated as targets for drug discovery in hematological malignancies (such as BCR-ABL and FLT3); other novel kinases hold considerable interest for targeted intervention: myeloid leukemias (KDR, KIT, CSF-1R, RAS and RAF), lymphoid leukemias (JAK2 fusion protein, TIE-1, CDK modulators), lymphoma (ALK, CDK modulators, mTOR), myeloproliferative disorders (PDGF-R or FGF-R fusion gene products, FGF-R1) and myeloma (FGF-R3, STAT3). Over the past five years, the number of kinase-targeted drug therapies undergoing clinical development has increased exponentially. This review will focus on novel kinase targets currently undergoing preclinical and clinical investigation.
...
PMID:Kinases as drug discovery targets in hematologic malignancies. 1630 89

Activating tyrosine kinase (TK) mutations disrupt cellular proliferation and survival pathways and are increasingly recognized as a fundamental cause of human cancers. Until very recently, the only TK mutations widely observed in myeloid neoplasia were the BCR/ABL1 fusions characteristic of chronic myeloid leukemia and some acute leukemias, and FLT3 activating mutations in a minority of acute myeloid leukemias. Several rare TK mutations are found in various atypical myeloproliferative disorders, but big pieces of the pathobiological puzzle were glaringly missing. In the first half of 2005, one gap was filled in: 7 studies identified the same acquired amino acid substitution (V617F) in the Janus kinase 2 (JAK2) TK in large numbers of patients with diverse clonal myeloid disorders. Most affected patients suffer from the classic BCR/ABL1-negative myeloproliferative disorders (MPD), especially polycythemia vera (74% of n = 506), but a subset of people with essential thrombocythemia (36% of n = 339) or myelofibrosis with myeloid metaplasia (44% of n = 127) bear the identical mutation, as do a few individuals with myelodysplastic syndromes or an atypical myeloid disorder (7% of n = 556). This long-sought common mutation in BCR/ABL1-negative MPD raises many provocative biological and clinical questions, and demands re-evaluation of prevailing diagnostic algorithms for erythrocytosis and thrombocytosis. JAK2 V617F may provide novel molecular targets for drug therapy, and suggests other places to seek cooperating mutations or mutations associated with similar phenotypes. The story of this exciting finding will unfold rapidly in the years ahead, and ongoing developments will be important for all hematologists to understand.
...
PMID:JAK2 V617F in myeloid disorders: what do we know now, and where are we headed? 1632 48

Chronic neutrophilic leukemia (CNL) is a rare disease and can cause considerable diagnostic difficulty. Although the V617F JAK2 mutation has been described by several groups to be associated with classical myeloproliferative disorders (MPD), this same mutation has been detected with a low incidence in atypical MPD, such as CNL. Here we report the presence of the V617F mutation in a CNL patient, who is unusual for having survived for more than 96 months, with little disease progression. It remains to be established what role this mutation, which gives cells a proliferative advantage, might play in the pathogenesis and prognosis of rare atypical MPD.
...
PMID:Chronic neutrophilic leukemia with an associated V617F JAK2 tyrosine kinase mutation. 1633 Apr 46

A recurrent somatic activating mutation in the nonreceptor tyrosine kinase JAK2 (JAK2V617F) occurs in the majority of patients with the myeloproliferative disorders polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, and, less commonly, chronic myelomonocytic leukemia. We do not understand the basis for the specificity of the JAK2V617F mutation in clonal disorders of the myeloid, but not lymphoid, lineage, nor has the basis for the pleiotropic phenotype of JAK2V617F-associated myeloproliferative disorders been delineated. However, the presence of the identical mutation in patients with related, but clinicopathologically distinct, myeloid disorders suggests that interactions between the JAK2V617F kinase and other signaling molecules may influence the phenotype of hematopoietic progenitors expressing JAK2V617F. Here, we show that coexpression of the JAK2V617F mutant kinase with a homodimeric Type I cytokine receptor, the erythropoietin receptor (EpoR), the thrombopoietin receptor, or the granulocyte colony-stimulating-factor receptor, is necessary for transformation of hematopoietic cells to growth-factor independence and for hormone-independent activation of JAK-STAT signaling. Furthermore, EpoR mutations that impair erythropoietin-mediated JAK2 or STAT5 activation also impair transformation mediated by the JAK2V617F kinase, indicating that JAK2V617F requires a cytokine receptor scaffold for its transforming and signaling activities. Our results reveal the molecular basis for the prevalence of JAK2V617F in diseases of myeloid lineage cells that express these Type I cytokine receptors but not in lymphoid lineage cells that do not.
...
PMID:Expression of a homodimeric type I cytokine receptor is required for JAK2V617F-mediated transformation. 1636 88

We studied the relationship between granulocyte JAK2 (V617F) mutation status, circulating CD34(+) cells, and granulocyte activation in myeloproliferative disorders. Quantitative allele-specific polymerase chain reaction (PCR) showed significant differences between various disorders with respect to either the proportion of positive patients (53%-100%) or that of mutant alleles, which overall ranged from 1% to 100%. In polycythemia vera, JAK2 (V617F) was detected in 23 of 25 subjects at diagnosis and in 16 of 16 patients whose disease had evolved into myelofibrosis; median percentages of mutant alleles in these subgroups were significantly different (32% versus 95%, P < .001). Circulating CD34(+) cell counts were variably elevated and associated with disease category and JAK2 (V617F) mutation status. Most patients had granulocyte activation patterns similar to those induced by administration of granulocyte colony-stimulating factor. A JAK2 (V617F) gene dosage effect on both CD34(+) cell counts and granulocyte activation was clearly demonstrated in polycythemia vera, where abnormal patterns were mainly found in patients carrying more than 50% mutant alleles. These observations suggest that JAK2 (V617F) may constitutively activate granulocytes and by this means mobilize CD34(+) cells. This exemplifies a novel paradigm in which a somatic gain-of-function mutation is initially responsible for clonal expansion of hematopoietic cells and later for their abnormal trafficking via an activated cell progeny.
...
PMID:Relation between JAK2 (V617F) mutation status, granulocyte activation, and constitutive mobilization of CD34+ cells into peripheral blood in myeloproliferative disorders. 1637 57


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

---