Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0032463 (polycythemia vera)
 3,374 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Myelofibrosis (MF; primary or post-polycythemia vera/essential thrombocythemia) carries the worst prognosis among BCR-ABL-negative myeloproliferative neoplasms (MPNs). Stem cell transplantation is the only curative approach but is hampered by significant nonrelapse mortality. Thus, effective, targeted therapies are needed. A mutated Janus kinase 2 (JAK2) gene (JAK2(V617F)), found in a significant portion of patients with MPN, results in increased JAK2 tyrosine kinase activity, leading to clonal proliferation; several small molecules inhibit the growth of hematopoietic colonies harboring JAK2(V617). Several JAK2 inhibitors have reached the clinical trial stage and are reviewed here. The most developed among them is INCB018424, which has demonstrated noteworthy clinical activity, with a rapid and profound reduction in splenomegaly and associated improvement in constitutional symptoms in MF patients receiving 10-25 mg orally twice daily, continuously. Thrombocytopenia (reversible) was the most common adverse event, seen in 30% of patients treated with 25 mg twice daily but not with 10 mg twice daily. Interestingly, INCB018424 was equally active in patients with and without JAK2 mutation. Other JAK2 inhibitors are less developed but show a similar type of clinical benefit. Conclusively, JAK2 inhibitors, particularly INCB018424, are clinically active in MF and are well tolerated. Whether they have an effect on the natural course of MF in treated patients remains to be elucidated.
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PMID:JAK2 inhibitors: A reality? A hope? 1977 62

Splenic enlargement (splenomegaly) develops in numerous disease states, although a specific pathogenic role for the spleen has rarely been described. In polycythemia vera (PV), an activating mutation in Janus kinase 2 (JAK2(V617)) induces splenomegaly and an increase in hematocrit. Splenectomy is sparingly performed in patients with PV, however, due to surgical complications. Thus, the role of the spleen in the pathogenesis of human PV remains unknown. We specifically tested the role of the spleen in the pathogenesis of PV by performing either sham (SH) or splenectomy (SPL) surgeries in a murine model of JAK2(V617F)-driven PV. Compared to SH-operated mice, which rapidly develop high hematocrits after JAK2(V617F) transplantation, SPL mice completely fail to develop this phenotype. Disease burden (JAK2(V617)) is equivalent in the bone marrow of SH and SPL mice, however, and both groups develop fibrosis and osteosclerosis. If SPL is performed after PV is established, hematocrit rapidly declines to normal even though myelofibrosis and osteosclerosis again develop independently in the bone marrow. In contrast, SPL only blunts hematocrit elevation in secondary, erythropoietin-induced polycythemia. We conclude that the spleen is required for an elevated hematocrit in murine, JAK2(V617F)-driven PV, and propose that this phenotype of PV may require a specific interaction between mutant cells and the spleen.
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PMID:Splenectomy normalizes hematocrit in murine polycythemia vera. 1978 10

Polycythemia vera (PV) and essential thrombocythemia (ET) are chronic myeloproliferative disorders characterized by an increased incidence of thrombo-hemorrhagic complications. The acquired somatic Janus kinase 2 (JAK2) V617F mutation is present in the majority of PV and ET patients. Because aberrant protein Tyr-phosphorylation has been associated with hematopoietic malignancies, the activity of the tyrosine kinases Src and JAK2 was analyzed in resting and thrombin-stimulated platelets from 13 PV and 42 ET patients. JAK2 was found inactive in healthy and pathological resting cells regardless of the V617F mutation. In addition, Src was inactive in all resting platelets, but in the pathological specimens it was present in a preactivated conformation as a consequence of anomalous dephosphorylation of its inhibitory phospho-Tyr527 residue, likely mediated by Src homology-2 domain-containing protein Tyr-phosphatase-2 (SHP-2), whose constitutive activity correlated with its recruitment to Src. Low thrombin concentration triggered a more rapid Src-signaling activation, higher [Ca(2+)](c) increase, and aggregation in pathological platelets compared with controls. Thrombin-induced Src activation preceded JAK2 activation, which occurred simultaneously in normal and pathological platelets. Our results indicate that a constitutive Src kinase preactivation is implicated in platelet hypersensitivity and likely involved, at least partially, in the functional abnormalities of PV and ET platelets.
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PMID:Src tyrosine kinase preactivation is associated with platelet hypersensitivity in essential thrombocythemia and polycythemia vera. 1996 50

The myeloproliferative disorders polycythemia vera, essential thrombocytosis, and primary myelofibrosis are clonal disorders arising in a pluripotent hematopoietic stem cell, causing an unregulated increase in the number of erythrocytes, leukocytes, or platelets, alone or in combination; eventual marrow dominance by the progeny of the involved stem cell; and a tendency to arterial or venous thrombosis, marrow fibrosis, splenomegaly, or transformation to acute leukemia, albeit at widely varying frequencies. The discovery of an activating mutation (V617F) in the gene for JAK2 (Janus kinase 2), a tyrosine kinase utilized by hematopoietic cell receptors for erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor, provided an explanation for the shared clinical features of these 3 disorders. Constitutive JAK2 activation provides a growth and survival advantage to the hematopoietic cells of the affected clone. Because signaling by the mutated kinase utilizes normal pathways, the result is overproduction of morphologically normal blood cells, an often indolent course, and (in essential thrombocytosis) usually a normal life span. Because the erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor receptors are all constitutively activated, polycythemia vera is the potential ultimate clinical phenotype of the JAK2 V617F mutation and, as a corollary, is the most common of the 3 disorders. The number of cells expressing the JAK2 V617F mutation (the allele burden) seems to correlate with the clinical phenotype. Preliminary results of clinical trials with agents that inhibit the mutated kinase indicate a reduction in splenomegaly and alleviation of night sweats, fatigue, and pruritus.
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PMID:Narrative review: Thrombocytosis, polycythemia vera, and JAK2 mutations: The phenotypic mimicry of chronic myeloproliferation. 2019 36

A common somatic point mutation has recently been identified in the Janus kinase 2 (JAK2) gene in virtually all cases of polycythemia vera and in a majority of patients with essential thrombocythemia and idiopathic myelofibrosis. This common mutation in the pseudokinase autoinhibitory domain of the enzyme results in constitutive tyrosine kinase activation, which in turn leads to cytokine hypersensitivity and factor independence in factor-dependent cell lines, and causes polycythemia in mice. This discovery has led to greater understanding of the molecular pathogenesis of the chronic myeloproliferative disorders, which may translate into targeted therapy.
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PMID:The JAK2(V617F) tyrosine kinase mutation in myeloproliferative disorders: Summary of published literature and a perspective. 2042 35

Myeloproliferative neoplasms (MPNs) originate from genetically transformed hematopoietic stem cells that retain the capacity for multilineage differentiation and effective myelopoiesis. Beginning in early 2005, a number of novel mutations involving Janus kinase 2 (JAK2), Myeloproliferative Leukemia Virus (MPL), TET oncogene family member 2 (TET2), Additional Sex Combs-Like 1 (ASXL1), Casitas B-lineage lymphoma proto-oncogene (CBL), Isocitrate dehydrogenase (IDH) and IKAROS family zinc finger 1 (IKZF1) have been described in BCR-ABL1-negative MPNs. However, none of these mutations were MPN specific, displayed mutual exclusivity or could be traced back to a common ancestral clone. JAK2 and MPL mutations appear to exert a phenotype-modifying effect and are distinctly associated with polycythemia vera, essential thrombocythemia and primary myelofibrosis; the corresponding mutational frequencies are approximately 99, 55 and 65% for JAK2 and 0, 3 and 10% for MPL mutations. The incidence of TET2, ASXL1, CBL, IDH or IKZF1 mutations in these disorders ranges from 0 to 17%; these latter mutations are more common in chronic (TET2, ASXL1, CBL) or juvenile (CBL) myelomonocytic leukemias, mastocytosis (TET2), myelodysplastic syndromes (TET2, ASXL1) and secondary acute myeloid leukemia, including blast-phase MPN (IDH, ASXL1, IKZF1). The functional consequences of MPN-associated mutations include unregulated JAK-STAT (Janus kinase/signal transducer and activator of transcription) signaling, epigenetic modulation of transcription and abnormal accumulation of oncoproteins. However, it is not clear as to whether and how these abnormalities contribute to disease initiation, clonal evolution or blastic transformation.
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PMID:Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. 2042 94

Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs) are characterized by stem cell-derived, unrestrained clonal myeloproliferation. The World Health Organization classification system, proposed in 2008, identifies 7 distinct categories of Ph-negative MPNs including essential thrombocythemia (ET); polycythemia vera (PV); primary myelofibrosis (PMF); mastocytosis; chronic eosinophilic leukemia; chronic neutrophilic leukemia; and MPN, unclassifiable. For many years, the treatment of ET, PV, and PMF, the most frequently diagnosed Ph-negative MPNs, has been largely supportive. In recent years, that paradigm has been challenged because of the discovery of a recurrent point mutation in the Janus kinase 2 (JAK2) gene (JAK2(V617F)). This mutation can be detected in the vast majority of patients with PV and approximately half of patients with ET or PMF and serves as both a diagnostic marker as well as representing a putative molecular target for drug development. Several putative targeted agents with significant in vitro JAK2 inhibitory activity and various degrees of JAK2 specificity are currently undergoing clinical evaluation. Furthermore, other investigational non-tyrosine kinase inhibitor approaches such as immunomodulatory agents and pegylated interferon- have also shown promising results in MPNs.
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PMID:Experimental therapeutics for patients with myeloproliferative neoplasias. 2092 95

The discovery of a common Janus kinase 2 (JAK2) point mutation, JAK2V617F, in myeloproliferative neoplasms has generated enormous interest in the development and therapeutic use of small molecule JAK2 inhibitor-targeted therapy in these diseases. A handful of compounds are currently in clinical development in primary myelofibrosis or post-polycythemia vera (PV)/essential thrombocythemia (ET) myelofibrosis. To date, clinical benefit has been demonstrated in terms of reduction of splenomegaly, improvement in constitutional symptoms, and control of leukocytosis. Some of the drugs have also been evaluated in PV and ET, with demonstrated activity against erythrocytosis, thrombocytosis, pruritus, and splenomegaly. However, drug effect on bone marrow fibrosis or JAK2 allele burden has been modest so far. Regardless, it is important to keep in mind that current anti-JAK2 treatment trials constitute only the beginning of many upcoming similar clinical trials, and that it is premature to make generalizations or any form of comparative conclusions regarding drug activity or toxicity.
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PMID:Preclinical and clinical activity of ATP mimetic JAK2 inhibitors. 2096 92

The extent of red blood cell adhesion is correlated with the incidence of vascular complications and the severity of the disease. Patients with sickle cell anemia (HbSS) experience vasoocclusive episodes. The adhesion of RBCs from HbSS patients is increased and related to VLA-4 exposure, which binds to vascular cell adhesion molecule (VCAM-1). Inter Cellular Adhesion Molecule (ICAM-1), CD31, CD36 and glycans are potential receptors for PfEMP1 of RBCs parasited by plasmodium falciparum. The incidence of vascular complications is very high in patients with diabetes mellitus. RBC adhesion is increased and statistically correlated with the severity of the angiopathy. Glycation of RBC membrane proteins is responsible for binding to the receptor for advanced glycation end products (RAGE). Polycythemia Vera (PV) is the most frequent myeloproliferative disorder and characterized by a high occurrence of thrombosis of mesenteric and cerebral vessels. PV is due to a mutation of the Janus kinase 2 (JAK2 V617F). This mutation stimulates erythropoiesis and is the cause of Lu/BCAM (CD239) phosphorylation, which potentiated the interaction with laminin alpha 5. The couple laminin alpha 5 endothelial and phosphorylated Lu/BCAM explained the increased adhesion of RBCs from patients PV to endothelium.
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PMID:[Molecular basis of red blood cell adhesion to endothelium]. 2129 12

The JAK2V617F mutation has been identified in most patients with myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia and primary myelofibrosis. Although JAK2V617F is the predominant allele associated with MPNs, other activating Janus kinase 2 (JAK2) alleles (such as K539L, T875N) also have been identified in distinct MPNs. The basis for the differences in the in vivo effects of different JAK2 alleles remains unclear. We have characterized three different classes of disease-associated JAK2 mutants (JAK2V617F, JAK2K539L and JAK2T875N) and found significant differences in biochemical, signaling and transforming properties among these different classes of JAK2 mutants.
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PMID:Differential biological activity of disease-associated JAK2 mutants. 2136 19


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