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)

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm that may display a variable degree of cytopenia and dysplasia sometimes difficult to distinguish from myelodysplastic syndrome with myelofibrosis (MDS-MF). We reviewed flow cytometric features of bone marrow from 70 cases of PMF and compared them with those from 17 cases of MDS-MF and 20 nonneoplastic control cases. The results were correlated with JAK2(V617F) and cytogenetic findings. Granulocytes and monocytes from PMF cases exhibited multiple dysplastic features overlapping with those of MDS-MF at a comparable or higher frequency: low side scattering, aberrant CD56 expression in granulocytes and monocytes, and an abnormal CD13/CD16 maturation pattern. Unique to PMF was the small granulocyte size compared with that of MDS-MF and control cases. Although the percentage of CD56+ granulocytes and monocytes did not correlate with JAK2(V617F) or cytogenetic abnormalities, a subset analysis of 36 cases revealed that median fluorescence intensity of CD56 expression correlated positively with the presence of cytogenetic abnormalities. Our findings indicate that although there is considerable overlap between PMF and MDS-MF, the smaller granulocytes observed in PMF are a useful distinguishing feature.
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PMID:Aberrant myeloid maturation identified by flow cytometry in primary myelofibrosis. 2009 42

Approximately 50% of essential thrombocythaemia and primary myelo-fibrosis patients do not have a JAK2 V617F mutation. Up to 5% of these are reported to have a MPL exon 10 mutation but testing for MPL is not routine as there are multiple mutation types. The ability to routinely assess both JAK2 and MPL mutations would be beneficial in the differential diagnosis of unexplained thrombocytosis or myelofibrosis. We developed and applied a high resolution melt (HRM) assay, capable of detecting all known MPL mutations in a single analysis, for the detection of MPL exon 10 mutations. We assessed 175 ET and PMF patients, including 67 that were JAK2 V617F-negative by real time polymerase chain reaction (PCR). Overall, 19/175 (11%) patients had a MPL exon 10 mutation, of whom 16 were JAK2 V617F-negative (16/67; 24%). MPL mutation types were W515L (11), W515K (4), W515R (2) and W515A (1). One patient had both W515L and S505N MPL mutations and these were present in the same haemopoietic colonies. Real time PCR for JAK2 V617F analysis and HRM for MPL exon 10 status identified one or more clonal marker in 71% of patients. This combined genetic approach increases the sensitivity of meeting the World Health Organization diagnostic criteria for these myeloproliferative neoplasms.
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PMID:Clinical utility of routine MPL exon 10 analysis in the diagnosis of essential thrombocythaemia and primary myelofibrosis. 2015 76

Myelofibrosis shows a progressive clinical course and usually a poor, lethal prognosis. Allogeneic transplantation is an effective, potentially curable treatment approach although only a minority of patients may currently benefit from it. New effective treatment strategies are becoming available for this disease, including not only JAK2 inhibitors, but also other innovative drugs, targeting more general oncogenic mechanisms and the epigenetic control of cell proliferation and differentiation.
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PMID:Therapy of myelofibrosis (excluding JAK2 inhibitors). 2017 12

Janus kinases (JAKs) are critical components of cytokine signaling pathways which regulate immunity, inflammation, hematopoiesis, growth, and development. The recent discovery of JAK2-activating mutations as a causal event in the majority of patients with Philadelphia chromosome negative (Ph-) myeloproliferative disorders (MPDs) prompted many pharmaceutical companies to develop JAK2-selective inhibitors for the treatment of MPDs. JAK2 inhibitors effectively reduce JAK2-driven phosphorylation of signal transducer and activator of transcription 5, and cell proliferation and cell survival in JAK2-activated cells in vitro and in vivo. Most inhibitors are currently being evaluated in patients with one form of MPD, myelofibrosis. Patients treated with these inhibitors experienced a rapid reduction of splenomegaly, significant improvement of constitutional symptoms, and increased daily activity with few adverse events. A partial reduction of JAK2V617F disease burden during the treatment with JAK2 inhibitors was also observed. The inhibitors appear to have a therapeutic benefit in the treatment of these disorders. The results of ongoing clinical trials will allow further evaluation of clinical benefits and safety of these compounds. In this review, the authors summarize the status of JAK2 inhibitors in development and discuss their benefits and challenges.
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PMID:The current status and the future of JAK2 inhibitors for the treatment of myeloproliferative diseases. 2019 31

The diagnostic value of JAK2 mutational analysis in myeloproliferative neoplasms (MPN) is now well established and endorsed by the World Health Organization classification system for hematologic malignancies. The current review is focused on the prognostic impact and therapeutic relevance of JAK2 and other MPN-associated mutations in polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Mutations involving JAK2, MPL, TET2, and ASXL1 are discussed. In general, within a specific disease category, the mere presence or absence of any one of these mutations does not appear to correlate with survival or development of blast phase disease, myelofibrosis, or thrombosis. In contrast, interesting associations between JAK2V617F allele burden and clinical outcome (e.g. lower quartile range allele burden and shorter survival in PMF and higher allele burden and fibrotic transformation in PV) have been made, but require further validation, and their impact on treatment choices is not clear. Similarly, although detection of JAK2V617F status post allogeneic hematopoietic cell transplant indicates minimal residual disease, the general use of mutant allele burden for monitoring treatment response has not been systematically studied. Current information on mutational status and response to JAK2 inhibitor drug therapy is too preliminary to draw any conclusions.
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PMID:Mutational analysis in BCR-ABL-negative classic myeloproliferative neoplasms: impact on prognosis and therapeutic choices. 2021 47

Activating alleles of Janus kinase 2 (JAK2) such as JAK2(V617F) are central to the pathogenesis of myeloproliferative neoplasms (MPN), suggesting that small molecule inhibitors targeting JAK2 may be therapeutically useful. We have identified an aminopyrimidine derivative (CYT387), which inhibits JAK1, JAK2, and tyrosine kinase 2 (TYK2) at low nanomolar concentrations, with few additional targets. Between 0.5 and 1.5muM CYT387 caused growth suppression and apoptosis in JAK2-dependent hematopoietic cell lines, while nonhematopoietic cell lines were unaffected. In a murine MPN model, CYT387 normalized white cell counts, hematocrit, spleen size, and restored physiologic levels of inflammatory cytokines. Despite the hematologic responses and reduction of the JAK2(V617F) allele burden, JAK2(V617F) cells persisted and MPN recurred upon cessation of treatment, suggesting that JAK2 inhibitors may be unable to eliminate JAK2(V617F) cells, consistent with preliminary results from clinical trials of JAK2 inhibitors in myelofibrosis. While the clinical benefit of JAK2 inhibitors may be substantial, not the least due to reduction of inflammatory cytokines and symptomatic improvement, our data add to increasing evidence that kinase inhibitor monotherapy of malignant disease is not curative, suggesting a need for drug combinations to optimally target the malignant cells.
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PMID:CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms. 2038 88

Polycythemia vera is a myeloproliferative disease, which, if untreated, leads to thrombohemorrhagic complications and eventually to progressive myelofibrosis, anemia, and splenomegaly. Two newly available drugs, interferon alfa and imatinib mesylate, may alter the course of this disease. Used as single agents, each produces lasting remissions in about 75% of patients with polycythemia vera. Of significance, change in JAK2 expression has been reported after treatment with both agents.
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PMID:Update on the treatment of polycythemia vera with recombinant interferon alfa or imatinib mesylate. 2042 87

Managing patients with myelofibrosis (MF)-either those with primary MF or those whose MF has evolved from antecedent polycythemia vera or essential thrombocythemia-presents many challenges to the hematologist. Cure is potentially achievable through allogeneic stem cell transplantation, but this therapy is either inappropriate or not feasible for most patients. MF patients suffer from a range of debilitating disease manifestations (eg, massive splenomegaly, cytopenias, constitutional symptoms, and transformation to a treatment-refractory blast phase). Currently available therapies are palliative but can be of significant value to some MF patients for anemia, splenomegaly, or sometimes both manifestations. New medical therapies for MF revolve around three main themes: immunomodulation (to assist anemia), hypomethylation strategies, and (the most robust pipeline) the use of targeted JAK2 inhibitors. These latter agents have shown the ability to improve MF-associated splenomegaly and MF-associated symptoms but do not improve (and may exacerbate) anemia or thrombocytopenia. Future targeted agents, and perhaps combinations of agents that currently show complementary benefits, are anticipated to further enhance the efficacy of medical therapy for MF.
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PMID:New drugs for the treatment of myelofibrosis. 2042 92

Several international working groups cooperated to propose new diagnostic guidelines for polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) to the steering committee of the World Health Organization. Because JAK2 mutation status presents a decisive diagnostic test in PV, this feature was introduced as a major criterion. Minor criteria, such as characteristic bone marrow morphology, low erythropoietin level, and erythroid colony formation, were kept as supporting parameters. In PMF, major diagnostic criteria were established by histologic features independent of the presence of relevant fibrosis or myelofibrosis with myeloid metaplasia. JAK2 mutation status was restricted to positive findings to exclude reactive myelofibrosis. A decrease in the platelet level was proposed for ET, because vascular complications may occur at lower platelet counts. As with PMF, morphology plays a distinctive role in diagnosis, particularly for its differentiation from early-stage PV or prodromal PMF associated with thrombocytosis.
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PMID:The 2008 WHO diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis. 2042 36

Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm that involves primarily the megakaryocytic lineage. After many years, a few patients with ET may develop bone marrow (BM) fibrosis and rarely develop osteosclerosis. A 60-yr-old female was admitted due to severe left upper quadrant abdominal discomfort. She had been diagnosed as ET 19 yrs ago. On liver computed tomography severe splenomegaly was shown. Laboratory tests revealed WBC 24.3x10(9)/L, hemoglobin 13.4 g/dL, platelets 432x10(9)/L, lactate dehydrogenase 4,065 IU/L (reference range; 240-480). Blood smear demonstrated leukoerythroblastosis, teardrop cells, and giant and hypogranular platelets. BM study revealed inadequate aspirate due to dry tap. BM biopsy showed clusters of dysplastic megakaryocytes, grade 3 fibrosis, and severe osteosclerosis. Major/minor BCR-ABL1 rearrangement and JAK2 V617F mutation were not detected. Cytogenetic studies revealed normal karyotype. According to the 2008 WHO diagnostic criteria, the patient was diagnosed as having post-essential thrombocythemia myelofibrosis with severe osteosclerosis.
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PMID:[A case of post-essential thrombocythemia myelofibrosis with severe osteosclerosis]. 2044 28


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