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)

Signal transducer and activator of transcription (STAT) proteins are phosphorylated and activated by Janus kinases (JAKs). Recently, several groups identified a recurrent somatic point mutation constitutively activating the hematopoietic growth factor receptor-associated JAK2 tyrosine kinase in diverse chronic myeloid disorders - most commonly classic myeloproliferative disorders (MPD), especially polycythemia vera. We hypothesized that the JAK2 V617F mutation might also be present in samples from patients with acute myeloid leukemia (AML), especially erythroleukemia (AML-M6) or megakaryoblastic leukemia (AML-M7), where it might mimic erythropoietin or thrombopoietin signaling. First, we documented STAT3 activation by immunoblotting in AML-M6 and other AML subtypes. Immunoperoxidase staining confirmed phosphorylated STAT3 in malignant myeloblasts (21% of cases, including all AML-M3 samples tested). We then analyzed genomic DNA from 162 AML, 30 B-cell lymphoma, and 10 chronic lymphocytic leukemia (CLL) samples for JAK2 mutations, and assayed a subset for SOCS1 and FLT3 mutations. Janus kinase2 V617F was present in 13/162 AML samples (8%): 10/13 transformed MPD, and three apparent de novo AML (one of 12 AML-M6, one of 24 AML-M7, and one AML-M2 - all mixed clonality). FLT3 mutations were present in 5/32 (16%), while SOCS1 mutations were totally absent. Lymphoproliferative disorder samples were both JAK2 and SOCS1 wild type. Thus, while JAK2 V617F is uncommon in de novo AML and probably does not occur in lymphoid malignancy, unexplained STAT3 activation is common in AML. Janus kinase2 extrinsic regulators and other proteins in the JAK-STAT pathway should be interrogated to explain frequent STAT activation in AML.
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PMID:JAK2 V617F is a rare finding in de novo acute myeloid leukemia, but STAT3 activation is common and remains unexplained. 1659 6

Polycythemia vera (PV) is a hematopoietic stem cell disorder characterized by a predominant proliferation of the erythroid cell line. The diagnosis is commonly based on the WHO criteria. The acquired V617F mutation in the tyrosine kinase gene JAK2 represents a new molecular marker proving clonality in PV and other chronic myeloproliferative disorders. Phlebotomy is still the treatment of choice to reduce the red cell mass. Low-dose acetylsalicylic acid is successful in the primary prophylaxis of vascular complications. However, the majority of patients require myelosuppressive therapy during the course of their disease due to progressive myeloproliferation. Hydroxyurea still plays a role in patients of all age groups. Interferon alpha represents an alternative, particularly for younger patients. Apart from sporadic cases of bone marrow transplantation, there is no known curative treatment in PV. To date, the diagnosis of PV was based mainly on clinical criteria. The identification of the JAK2 mutation enables new approaches to the diagnosis, classification, and treatment of PV and of the other myeloproliferative disorders.
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PMID:Diagnosis and therapy of polycythemia vera. 1667 81

Pathogenetically fundamental observations have identified polycythemia vera (PV) as a clonal stem cell disease with bone marrow histological and other biological features that distinctly differentiate it from other causes of 'increased' hematocrit. However, relatively little attention has been given to the effective utilization of pathology and laboratory markers of clonal myeloproliferation as diagnostic tools in PV. In contrast, the diagnostic use of red cell mass (RCM) measurement in PV stemmed from the accidental endorsement, as 'diagnostic criteria', of 'study eligibility criteria' that were formulated for clinical trials. It has since become evident that RCM measurement is a tedious procedure that is fraught with multiple-level imprecision, as well as suboptimal diagnostic accuracy. Therefore, it is reasonable to consider dispensing with RCM measurement as a diagnostic test for PV and instead utilize a diagnostic algorithm that combines clinical information with easily accessible laboratory data, including serum erythropoietin level and bone marrow histology. Recent discoveries of myeloproliferative-disease-specific molecular markers, including the JAK2 V617F tyrosine kinase mutation that is found in the majority of patients with PV, provide further support for such a measure.
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PMID:The diagnosis of polycythemia vera: new tests and old dictums. 1678 83

Exaggerated erythropoiesis and megakaryocytopoiesis are present at a variable extent in polycythemia vera (PV) and essential thrombocythemia (ET). With the recent discovery of the V617F mutation in the Janus kinase 2 (JAK2) tyrosine kinase in almost all cases of PV and in a subset of patients with ET, studies are now pending to assess the role of this mutation in the hematopoietic cell activation process and/or in the occurrence of thromboses in ET and PV. The JAK2 V617F point mutation makes the normal hematopoietic progenitor cells hypersensitive to thrombopoietin, erythropoietin, and myeloid progenitor cells, leading to trilinear hematopoietic myeloproliferation. This will have three main clinical consequences during long-term follow-up. First, spontaneous growth of enlarged mature megakaryocytes in ET/PV with overproduction of hypersensitive platelets results in a broad spectrum of platelet-mediated microvascular circulatory disturbances, which are very sensitive to low-dose aspirin. Second, spontaneous growth of erythropoiesis with the overproduction of erythrocytes leads to classic PV with increased hemoglobin, hematocrit, and red cell mass. This is associated with a high frequency of major arterial and venous thrombotic complications in addition to platelet-mediated microvascular circulatory disturbances of thrombocythemia. Third, the slowly progressive myeloid (granulocytic) metaplasia in bone marrow and spleen is complicated by secondary myelofibrosis caused by a megakaryocytic/granulocytic cytokine storm in about one fourth to one third of JAK2 V617F-positive PV patients after long-term follow-up, with no tendency of leukemic transformation as long as they are not treated with myelosuppressive agents. Randomized clinical trials directly comparing phlebotomy versus hydroxyurea or interferon alpha versus hydroxyurea in PV with progressive disease are lacking. Heterozygous V617F mutation is enough to produce the clinical picture of ET with a slight tendency to increased hemoglobin and hematocrit (early PV mimicking ET). Homozygous V617F mutation is associated with the clinical picture of classic PV and with a higher tendency to secondary myelofibrosis, but with no increased leukemia unless other biological or genetic factors come into play, such as myelosuppressive agents or the acquisition of additional biologic or genetic defects. Depending on the biological background of individual patients, heterozygous and homozygous JAK2 V617F ET/PV may preferentially induce myeloid metaplasia with myelofibrosis with a relative suppression of megakaryocytic and erythropoietic myeloproliferation leading to clinical pictures of fibrotic chronic idiopathic myelofibrosis (CIMF) or agnogenic myeloid metaplasia. The main conclusion is that JAK2 V617F is a 100% specific clue to a new distinct clonal myeloproliferative disorder. JAK2 V617F-positive ET/PV and CIMF should be distinguished from wild-type JAK2 ET, rare cases of PV, and CIMF, and should be evaluated during life-long follow-up.
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PMID:The role of JAK2 V617F mutation, spontaneous erythropoiesis and megakaryocytopoiesis, hypersensitive platelets, activated leukocytes, and endothelial cells in the etiology of thrombotic manifestations in polycythemia vera and essential thrombocythemia. 1681 Jun 14

The discovery of the activating V617F mutation in the JAK2 tyrosine kinase in a high proportion of patients with Ph- chronic myeloproliferative diseases (CMPD) represents a diagnostic breakthrough for these disorders. Trephine bone marrow biopsy is an essential part of the diagnostic workup of CMPD and represents a valuable archival source of DNA. Therefore, we studied 152 paraffin-embedded trephines with CMPD and related disorders for the presence of the V617F mutation, using both allele-specific polymerase chain reaction (PCR) and nested PCR with subsequent digestion with BsaXI. Only 6 of 152 (4%) samples were not evaluable because of poor DNA quality. The V617F mutation was detected in 27 of 28 (96%) cases of polycythemia vera, 17 of 23 (74%) cases of essential thrombocythemia, 28 of 45 (62%) cases of chronic idiopathic myelofibrosis, six of eight (75%) cases of CMPD unclassified, and two of four (50%) cases of myelodysplastic/myeloproliferative syndrome. Ph+ chronic myelogenous leukemia (four cases), reactive (secondary) erythrocytosis (14 cases), and thrombocytosis (one case) as well as normal controls (19 cases) all lacked the V617F mutation. Based on results of BsaXI digestion and sequencing, 24 of 54 (44%) evaluable V617F+ cases were considered homozygously mutated. Thus, detection of the V617F JAK2 mutation is feasible in paraffin-embedded trephine biopsies and represents a major advance in the diagnostic evaluation of CMPD.
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PMID:Detection of the activating JAK2 V617F mutation in paraffin-embedded trephine bone marrow biopsies of patients with chronic myeloproliferative diseases. 1682 1

The classical myeloproliferative disorders (MPDs) are comprised of the clonal, BCR-ABL-negative, chronic myeloid disorders of essential thrombocythemia, polycythemia vera, and myelofibrosis with myeloid metaplasia. Management of these disorders remains a significant challenge due to the varied range of prognosis and phenotypic manifestations. Curative therapy, achieved in some patients through allogeneic stem cell transplantation, is elusive or inappropriate in most. Additionally, no available medical therapy has been shown to clearly improve survival or delay disease progression. Current management involves an emphasis on prevention of thrombohemorrhagic complications (through aspirin treatment, phlebotomy and cytoreduction in high-risk patients) in early-stage patients and symptomatic care in those with advanced disease. Leukemic transformation from MPDs remains a rapidly fatal complication, unresponsive to current therapies. Recent elucidation of the role of the activating tyrosine kinase mutation JAK2 (V617F) is anticipated to usher in an era of greater understanding and targeted therapy for the MPDs.
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PMID:Practical management of classical myeloproliferative disorder patients: a clinician's guide. 1692 18

Diagnosis of the myeloproliferative disorders, polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF) is difficult due to lack of diagnostic markers. Recently, the acquisition of a mutation in the Janus kinase 2 (JAK2) gene by hemopoietic cells has been described as a genetic defect underlying myeloproliferative disorders. The mutation leads to constitutive activation of JAK2, a tyrosine kinase involved in cytokine receptor signalling. Because of the clinical importance of this mutation (JAK2 V617F) in diagnosing myeloproliferative disorders and its relevance for disease progression, we developed a semi-quantitative real-time PCR test to detect JAK2 V617F. With this assay, quantities down to 0.8% JAK2 V617F amongst wild-type DNA could reliably be detected. For quantification purposes, low intra- and inter-assay variabilities ensure good reproducibility of the assay. Thus the JAK2 V617F qPCR assay described here is quick, robust, simple and more sensitive than direct sequencing, RFLP, ARMS assay and other methods published so far to detect JAK2 V617F. We therefore believe that the assay will contribute to early diagnosis of myeloproliferative disorders and to disease management, especially when JAK2-specific inhibitors have become available for therapeutic use.
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PMID:A sensitive and reliable semi-quantitative real-time PCR assay to detect JAK2 V617F in blood. 1700 61

The chronic myeloproliferative disorders are clonal hematopoietic stem cell disorders of unknown etiology. In one of these (chronic myeloid leukemia), there is an associated pathognomonic chromosomal abnormality known as the Philadelphia chromosome. This leads to constitutive tyrosine kinase activity which is responsible for the disease and is used as a target for effective therapy. This review concentrates on the search in the other conditions (polycythemia vera, essential thrombocythemia and idiopathic mylofibrosis) for a similar biological marker with therapeutic potential. There is no obvious chromosomal marker in these conditions and yet evidence of clonality can be obtained in females by the use of X-inactivation patterns. PRV-1mRNA over expression, raised vitamin B12 levels and raised neutrophil alkaline phosphatase scores are evidence that cells in these conditions have received excessive signals for proliferation, maturation and reduced apoptosis. The ability of erythroid colonies to grow spontaneously without added external erythropoietin in some cases, provided a useful marker and a clue to this abnormal signaling. In the past year several important discoveries have been made which go a long way in elucidating the involved pathways. The recently discovered JAK2 V617F mutation which occurs in the majority of cases of polycythemia vera and in about half of the cases with the two other conditions, enables constitutive tyrosine kinase activity without the need for ligand binding to hematopoietic receptors. This mutation has become the biological marker for these conditions and has spurred the development of a specific therapy to neutralize its effects. The realization that inherited mutations in the thrombopoietin receptor (c-Mpl) can cause a phenotype of thrombocytosis such as in Mpl Baltimore (K39N) and in a Japanese family with S505A, has prompted the search for acquired mutations in this receptor in chronic myeloproliferative disease. Recently, two mutations have been found; W515L and W515K. These mutations have been evident in patients with essential thrombocythemia and idiopathic myelofibrosis but not in polycythemia vera. They presumably act by causing constitutional, activating conformational changes in the receptor. The discovery of JAK2 and Mpl mutations is leading to rapid advancements in understanding the pathophysiology and in the treatment of these diseases.
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PMID:Recent advances in the bcr-abl negative chronic myeloproliferative diseases. 1703 64

The chronic myeloproliferative diseases (CMDs) are a group of conditions characterized by unregulated blood cell production, that due either to excessive numbers of erythrocytes, leukocytes or platelets, or their defective function cause symptoms and signs of fatigue, headache, ruddy cyanosis, hemorrhage, abdominal distension, and the complications of vascular thrombosis. In the late 19th century Vaquez provided the first description of polycythemia vera (PV) and Hueck defined idiopathic myelofibrosis (IMF). In 1920, di Guglielmo established criteria for patients with essential thrombocythemia (ET). In 1951, Dameshek argued that these disorders, along with chronic myelogenous leukemia (CML) display many similar clinical and laboratory features [Dameshek W. Some speculations on the myeloproliferative syndromes. Blood 1951;6:372-5], and grouped them. In 2002, the World Health Organization expanded the definition of CMDs to also include chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia/hypereosinophilic syndrome (CEL/HES) and systemic mast cell disorder (SMCD) [Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 2002;100:2292-302]. While the molecular pathogenesis of CML is well known [Melo JV, Deininger MW. Biology of chronic myelogenous leukemia-signaling pathways of initiation and transformation. Hematol Oncol Clin North Am 2004;18:545-68], and the causes of CEL/HES and SMCD have been identified in about half of all cases [Gotlib J, Cools J, Malone III JM, Schrier SL, Gilliland DG, Coutre SE. The FIP1L1-PDGFRalpha fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: implications for diagnosis, classification, and management. Blood 2004; 103:2879-91; Valent P, Akin C, Sperr WR, Horny HP, Metcalfe DD. Mast cell proliferative disorders: current view on variants recognized by the World Health Organization. Hematol Oncol Clin North Am 2003; 17:1227-41], until very recently the etiologies of the three classically defined CMDs, PV, IMF and ET, were poorly understood. Each of these disorders is characterized by excessive hematopoiesis, a process usually dependent on one or more hematopoietic growth factors (HGFs). This review will focus on how our knowledge of the molecular mechanisms by which HGFs are produced, bind cell surface receptors and transduce survival and proliferative signals have provided the platform on which the multiple origins of CMDs can be understood and novel therapeutic interventions designed.
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PMID:Hematopoietic growth factors, signaling and the chronic myeloproliferative disorders. 1705 68

The identification of JAK2V617F mutations in polycythemia vera (PV), essential thrombocytosis (ET), and myelofibrosis (MF) represents an important advance in our understanding of these myeloproliferative disorders (MPD). Most, if not all, patients with PV and a significant number of patients with ET and MF are JAK2V617F positive, and the mutation likely arises in the hematopoietic stem cell compartment. JAK2V617F is a constitutively active tyrosine kinase that is able to activate JAK-STAT signaling most efficiently when co-expressed with the erythropoietin receptor (EPOR), the thrombopoietin receptor (MPL), or the granulocyte colony-stimulating factor receptor (GCSFR). Data from murine models supports the central role of JAK2V617F in the pathogenesis of MPD, as expression of JAK2V617F in a bone marrow transplantation assay results in polycythemia and myelofibrosis in recipient mice. Activation of JAK-STAT signaling by JAK2V617F in some, but not all MPD patients with ET and MF led to the identification of the constitutively active MPLW515L allele in ET and MF. Small molecule inhibitors of JAK-STAT signaling are currently being developed, which offer potential for molecularly targeted therapy for patients with PV, ET, and MF. Despite these advances, many questions remain regarding the role of a single disease allele in three phenotypically distinct MPD, the potential clinical efficacy of JAK2 inhibitors, and the identity of oncogenic alleles in JAK2V617F/MPLW515-negative MPD.
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PMID:Role of JAK-STAT signaling in the pathogenesis of myeloproliferative disorders. 1712 66


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