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

Micro RNA (miRNA) are small non-coding RNA molecules which have a post-transcriptional inhibitory regulation function, e.g. in megakaryopoiesis. A characteristic of Philadelphia chromosome-negative myeloproliferative neoplasm (Ph(-) MPN) is the abundance of morphologically aberrant megakaryocytes. Based on previously published in vitro megakaryocytic differentiation assay data, we selected miRNA 10a, 17-5p, 20a and 126 and potential target proteins (HOXA1, RUNX1) for analysis of laser-microdissected bone marrow megakaryocytes from Ph(-) MPN and controls (n=66). Furthermore, we tested a potential influence of cytoreductive treatment on miRNA expression in bone marrow cells during the course of Ph(-) MPN (n=18). In summary, miRNA 17-5p, 20a and 126 are constitutively expressed in Ph(-) MPN megakaryopoiesis while low or absent miRNA 10a appeared to correlate with strong megakaryocytic HOXA1 protein expression. No association to thrombocytosis, JAK2(V617F) mutations or cytoreductive treatment (bone marrow cells) were observed.
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PMID:Megakaryocytic expression of miRNA 10a, 17-5p, 20a and 126 in Philadelphia chromosome-negative myeloproliferative neoplasm. 1877 8

The World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues (2001) defined a provisional entity named refractory anemia with ringed sideroblasts associated to marked thrombocytosis (RARS-MT). Diagnosis of RARS-MT requires more than 15% of ringed sideroblasts in bone marrow aspirate and the existence of a thrombocytosis in blood, with a platelet count above 600 x 10(9)/L. Nevertheless, controversy exists regarding this platelet count "cut-off" value and, when RARS-MT was defined, the JAK2 mutation and its importance in the study of myeloproliferative disorders was unknown. We present the results of a Spanish retrospective multicentric study, which includes 76 cases of RARS with associated thrombocytosis (platelet count above 400 x 10(9)/L) at diagnosis (RARS-T), 36 of them with a platelet count above 600 x 10(9)/L. Our aim was to analyze their clinical, analytical and morphological characteristics, and to establish correlations with the JAK2 mutational status.
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PMID:Refractory anemia with ringed sideroblasts associated with thrombocytosis: comparative analysis of marked with non-marked thrombocytosis, and relationship with JAK2 V617F mutational status. 1882 Sep 95

Familial and acquired erythrocytosis and thrombocytosis are characterized by myeloid lineage hyperproliferation, which is either single or multi-lineage in origin. The single lineage disorders exhibit Mendelian inheritance with polyclonal hematopoiesis and often arise from a single genetic defect. In contrast, the multi-lineage disorders exhibit complex patterns of inheritance with multi-genetic origins and clonal hematopoiesis. They have the potential to acquire JAK2 somatic mutations, but this is not the primary event. Identification of the disease-causing genes will enable better classification of familial and acquired erythrocytosis and thrombocytosis. Furthermore, it will provide an insight into the mechanisms regulating myeloid cell proliferation.
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PMID:Genetic origins and clinical phenotype of familial and acquired erythrocytosis and thrombocytosis. 1900 25

Acquired sideroblastic anemia with unilineage dysplasia (WHO RARS) is a clonal stem cell disorder characterized by erythroid dysplasia, mitochondrial accumulation of mitochondrial ferritin, defective erythroid maturation and anemia. A fraction of these patients also show elevated platelet counts; since 2001 this has been defined as RARS with marked thrombocytosis (RARS-T). It has recently been described that around half of RARS-T patients, along with a small subset of other MDS and mixed myelodysplastic/ myeloproliferative disorders, carry the JAK2 mutation, and that MPL mutations are found in single patients. Clinically, RARS-T patients show features of both RARS, essential thrombocythmia (ET) and to some extent also myelofibrosis. However, the degree of anemia and overall survival is more similar to RARS than myeloproliferative disorders. The occurrence of JAK2 mutations and features of ET in RARS is too frequent to be the result of chance only, and it is possible that this link may provide a key to an increased understanding of the genetic abnormalities causing ring sideroblast formation.
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PMID:The role of JAK2 mutations in RARS and other MDS. 1907 58

Essential thrombocythemia (ET) is a hematopoietic disorder that manifests clinically as thrombocytosis, and patients with ET are at increased risk for developing thrombosis, myelofibrosis, and transformation to acute myeloid leukemia. Although ET was recognized as a distinct clinical syndrome more than 6 decades ago and was classified as a myeloproliferative neoplasm (MPN) by William Dameshek in 1951, the molecular pathogenesis of ET remained unknown until 2005, when activating mutations in the JAK2 tyrosine kinase (JAK2V617F) were identified in a significant proportion of patients with ET, polycythemia vera (PV) and primary myelofibrosis (PMF). In addition, subsequent studies have identified gain-of-function mutations in the thrombopoietin receptor (MPL) in a subset of patients with JAK2V617F-negative ET, suggesting that JAK2 activation by distinct mechanisms contributes to the pathogenesis of ET. Despite these important observations, important questions remain regarding the role of JAK2/MPL mutations in ET pathogenesis, the etiology of JAK2/MPL negative ET, the factors that distinguish ET from other MPNs with the JAK2V617F mutation, and the role of JAK2-targeted therapies for the treatment of these MPNs.
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PMID:New advances in the pathogenesis and therapy of essential thrombocythemia. 1907 62

Both the 2001 World Health Organisation (WHO) classification of haematopoietic neoplasms and the 2008 WHO classification revision include a distinctive diagnostic category, refractory anaemia with ring sideroblasts and thrombocytosis (RARS-T), to describe those rare patients who have both >or=15% ring sideroblasts and a sustained elevated platelet count. Recently, it has become clear that patients meeting WHO criteria for RARS-T have clonal JAK2(V617F) and MPL(W515) mutations at a similar rate to essential thrombocythaemia (ET). Given that the provisional classification of RARS-T as a myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap syndrome, rather than as a form of MPN (i.e., ET), rests principally upon the presence of ring sideroblasts, which are a non-specific morphological finding, these new molecular results prompt reconsideration of the necessity for a distinctive RARS-T category. Here we review the historical developments that led up the definition of RARS-T as a disease entity, and we discuss conceptual understanding of RARS-T and arguments against continued use of RARS-T as a separate diagnostic category.
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PMID:Is refractory anaemia with ring sideroblasts and thrombocytosis (RARS-T) a necessary or useful diagnostic category? 1912 Mar 70

We report two patients with peripheral vascular disease requiring multiple bilateral radiologic and surgical interventions, and whose disease was unresponsive to conventional anticoagulation and antiplatelet therapy. Although thrombocytosis was only intermittent, analysis of the Janus kinase 2 (JAK2) gene revealed a V617F mutation, thus confirming the presence of an underlying occult myeloproliferative disorder. We propose that JAK2 mutation analysis be considered in patients with recurrent, unexplained arterial events to identify those with occult myeloproliferative disorders.
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PMID:Recurrent refractory arterial thromboembolism associated with the Janus kinase 2 V617F mutation. 1917 56

The Janus kinase 2 (JAK2) V617F mutation has considerably helped understanding of the molecular pathogenesis of chronic myeloproliferative disorders (MPD), hence this study investigated for the first time the mutational status and relative quantitation of JAK2 V617F mRNA in Chinese patients with chronic MPD. The study cohort comprised 123 chronic MPD patients (35 with polycythaemia vera [PV], 85 with essential thrombocythaemia [ET], three with idiopathic myelofibrosis [IMF]). Blood samples examined by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and capillary electrophoresis showed that the prevalence of the JAK2 V617F mutation was 100%, 62.4% and 66.7% in PV, ET and IMF patients, respectively. The proportion of JAK2 V617F mutated mRNA was 89.5% in homozygotes and 57.9% in heterozygotes; 18 PV heterozygous patients showed significantly higher mutated JAK2 mRNA levels than 36 heterozygous ET patients. Six of 93 patients exhibited abnormal karyotypes, but specific chromosomal abnormality was not found. The combination of ARMS-PCR and capillary electrophoresis enables quantitative assay of JAK2 V617F mutation, which helps in chronic MPD diagnosis and estimation of minimal residual disease.
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PMID:Quantitative assay for Janus kinase 2 (JAK2) mutation in Chinese patients with chronic myeloproliferative disorders. 1921 72

To clarify the relationship between the levels of JAK2 wild-type (WT) and V617F mutant-positive platelets in patients with essential thrombocythaemia (ET), we quantified mutant levels in purified cells from 10 V617F-positive patients prior to receiving cytoreductive therapy. Mutant levels were significantly higher in platelet than neutrophil RNA (P = 0.002), but the mutation was still only present in a sub-population of platelets (median 54%). When the absolute number of WT platelets was calculated, it was always within or above the normal platelet range, indicating that there is an aberration in the negative feedback to JAK2 WT platelets in ET.
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PMID:The production of JAK2 wild-type platelets is not downregulated in patients with JAK2 V617F mutant-positive essential thrombocythaemia. 1922 78

Polycythemia vera (PV), essential thrombocythemia(ET), and primary myelofibrosis (PMF) share common clinical features, being clonal disorders of multipotent progenitors. In 2005, a somatic activating mutation in JAK2 (V617F) was identified in most patients with PV and in about half of patients with ET or PMF. The JAK2 mutation causes the constitutive activation of the JAK-STAT signaling pathway, and leads to autonomous cell growth in a cytokine-independent manner. A higher expression of JAK2 V617F would favor erythrocytosis, and a lower one would favor thrombocytosis. This may suggest that the expression levels of JAK2 V617F directly determine which cell lineages increase, possibly leading to the diversity of myeloproliferative diseases. Although only V617F JAK2 may cause myeloproliferative disease (MPD), clonogenic assay, analysis of familial MPD patients, and examination of JAK2 mutation in acute leukemia patients transformed from MPD show that there are additional somatic mutations which contribute to the pathogenesis of V617F JAK2 positive PV, ET, and PMF.
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PMID:[Myeloproliferative diseases caused by JAK2 mutation]. 1948 38


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