Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038002 (splenomegaly)
 9,873 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study describes portal vein thrombosis (PVT) in two women as the first and single presenting symptom of latent or masked myeloproliferative disease (MPD). Essential thrombocythemia (ET) was suspected by a sustained increase in platelet count (>400 x 10(9)/l) and slight splenomegaly on echogram. ET could be diagnosed by the presence of large platelet in peripheral blood smear, an increase in clustered large megakaryocytes in bone marrow smear and the presence of the JAK2(V617F) mutation. A subsequent biopsy specimen was consistent with the diagnosis of true ET. In patients with a first episode of splanchnic vein thrombosis (SVT), analysis of any venous thrombophilic risk factors as well as a JAK2(V617F) mutation status indicative for MPD is warranted. Administration of heparin followed by oral anticoagulation with vitamin K antagonists is the treatment of choice in patients with SVT. Anticoagulation therapy combined with low-dose aspirin and proper treatment of the MPD is recommended in patients with SVT associated with the JAK2(V617F) mutation.
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PMID:JAK2(V617F) positive early stage myeloproliferative disease (essential thrombocythemia) as the cause of portal vein thrombosis in two middle-aged women: therapeutic implications in view of the literature. 1768 55

Few investigators have evaluated the usefulness of the JAK2 V617F mutation for explaining the phenotypic variations and for predicting the risk of major clinical events in primary myelofibrosis (PMF). In a transversal survey we assayed by allele-specific polymerase chain reaction (PCR) the JAK2 V617F mutational status in 304 patients with PMF. Multiple DNA samples were collected prospectively from 64 patients, and a highly sensitive quantitative PCR was used as a confirmatory test. In a longitudinal prospective study we determined the progression rate to clinically relevant outcomes in 174 patients who had JAK2 mutation determined at diagnosis. JAK2 V617F was identified in 63.4% of patients. None of the V617F-negative patients who were sequentially genotyped progressed to become V617F positive, whereas progression rate from heterozygous to homozygous mutation was 10 per 100 patient-years. JAK2 V617F mutation contributed to hemoglobin, aquagenic pruritus, and platelet count variability, whereas homozygous mutation was independently associated with higher white blood cell count, larger spleen size, and greater need for cytoreductive therapies. Adjusting for conventional risk factors, V617F mutation independently predicted the evolution toward large splenomegaly, need of splenectomy, and leukemic transformation. We conclude that JAK2 V617F genotype should be considered in any future risk stratification of patients with PMF.
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PMID:JAK2 V617F mutational status predicts progression to large splenomegaly and leukemic transformation in primary myelofibrosis. 1771 47

Second malignancies after autologous haematopoietic stem-cell transplantation (AHSCT) are well-known long-term complications. We present a case of a 24-year-old male with relapsed Hodgkin lymphoma (HL) with no involvement of his bone marrow who underwent AHSCT. Four years later he developed mild anaemia and a computed tomography showed an enlarged spleen. As his anaemia worsened, a bone marrow was performed. There was no evidence of HL but intense reticular and collagen fibrosis with hypocellularity was detected. Cytogenetic studies could not obtain cells in metaphase in two occasions. PCR for V617F JAK2 mutation was positive. Until now, with 7 years of follow up from his diagnosis of myelofibrosis with myeloid metaplasia (MMM) he did not require specific treatment besides from red cell transfusions when anaemia worsened during a pneumocistis carinii infection. We present this case, because MMM is a infrequent second neoplasm after AHSCT. Revising the literature we could not find any case like this reported previously.
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PMID:Myelofibrosis with myeloid metaplasia in a patient with relapsed Hodgkin's lymphoma who underwent autologous hematopoietic stem cell transplantation. 1785 52

An acquired JAK2 V617F mutation is found in most patients with polycythemia vera (PV), and about half of patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF). Mice transplanted with bone marrow cells in which JAK2 V617F was retrovirally expressed developed PV-like features, but not ET or PMF. To address the contribution of this mutation to the pathogenesis of these three MPDs, we generated two lines of JAK2 V617F transgenic mice. One line showed granulocytosis after 4 months of age. Among 43 mice, 8 (19%) showed polycythemia and 15 (35%) showed thrombocythemia. The second line showed extreme leukocytosis and thromobocytosis. They showed anemia that means Hb value from 9 to 10 g per 100 ml when 1 month old. Myeloid cells and megakaryocytes were predominant in the bone marrow of these animals, and splenomegaly was observed. The expression of JAK2 V617F mRNA in bone marrow cells was 0.45 and 1.35 that of endogenous wild-type JAK2 in the two lines, respectively. In vitro analysis of bone marrow cells from both lines showed constitutive activation of ERK1/2, STAT5 and AKT, and augmentation of their phosphorylations by cytokine stimulation. We conclude that in vivo expression of JAK2 V617F results in ET-, PMF- and PV-like disease.
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PMID:Development of ET, primary myelofibrosis and PV in mice expressing JAK2 V617F. 1803 15

Idiopathic myelofibrosis is a type of chronic myeloproliferative disorders characterized by splenomegaly, a leukoerythroblastic blood picture, teardrop poikilocytosis, in various degrees of bone marrow fibrosis and extramedullary hematopoiesis. In this paper, the biological characters and pathogenesis of idiopathic myelofibrosis such as mutation of tyrosine kinase receptor, mutation of GABA transporter 1, JAK2 mutation and c-MPl mutation, as well as other pathogenesis related with idiopathic myelofibrosis were reviewed.
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PMID:[New insight into pathogenesis of idiopathic myelofibrosis--review]. 1808 95

The JAK2(V617F) mutation was found in most patients with myeloproliferative disorders (MPDs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis. We have generated transgenic mice expressing the mutated enzyme in the hematopoietic system driven by a vav gene promoter. The mice are viable and fertile. One line of the transgenic mice, which expressed a lower level of JAK2(V617F), showed moderate elevations of blood cell counts, whereas another line with a higher level of JAK2(V617F) expression displayed marked increases in blood counts and developed phenotypes that closely resembled human essential thrombocythemia and polycythemia vera. The latter line of mice also developed primary myelofibrosis-like symptoms as they aged. The transgenic mice showed erythroid, megakaryocytic, and granulocytic hyperplasia in the bone marrow and spleen, displayed splenomegaly, and had reduced levels of plasma erythropoietin and thrombopoietin. They possessed an increased number of hematopoietic progenitor cells in peripheral blood, spleen, and bone marrow, and these cells formed autonomous colonies in the absence of growth factors and cytokines. The data show that JAK2(V617F) can cause MPDs in mice. Our study thus provides a mouse model to study the pathologic role of JAK2(V617F) and to develop treatment for MPDs.
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PMID:Transgenic expression of JAK2V617F causes myeloproliferative disorders in mice. 1833 77

E-proteins are a class of helix-loop-helix (HLH) proteins, which play multiple roles throughout lymphoid development. The DNA binding activities of the E-proteins are regulated by a distinct class of antagonistic HLH proteins, named Id1-4. Here we demonstrate that Id2 deficient mice in a C57BL/6 genetic background exhibit increased cellularity in the granulocyte/myeloid progenitor compartment and show significantly higher numbers of maturing neutrophils. Within 6 months of age, Id2 deficient mice succumbed from overwhelming granulocytosis. The disease closely mimicked the distinctive features of human chronic myeloid leukemia: leukocytosis with maturing neutrophils, splenomegaly, hepatomegaly, and myeloid infiltration into peripheral tissues, including spleen, liver, and lungs. Strikingly, forced Id2 expression in murine bone marrow cells substantially delayed the onset of myeloproliferative disease (MPD). Collectively, these studies show that suppression of E-protein activity interferes with the development of BCR-ABL-mediated MPD.
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PMID:Suppression of E-protein activity interferes with the development of BCR-ABL-mediated myeloproliferative disease. 1872 23

Interferon (IFN) was the first cytokine discovered 50 years ago, with a wide range of biological properties, including immunomodulatory, proapoptotic and antiangiogenic activities, that rapidly raised interest in its therapeutic use in malignancies. IFN-receptor characterization was also pivotal in the discovery of the JAK/STAT signaling pathway. Among the large IFN family, mainly one of the type I IFN, IFN-alpha2, is used in therapy. Many clinical trials have shown remarkable efficacy of IFN-alpha in bcr-abl-negative myeloproliferative neoplasms (MPNs), especially polycythemia vera (PV), and essential thrombocythemia (ET). IFN-alpha induces about 80% of hematological responses in those diseases and is able to reduce splenomegaly, as well as relieve pruritus and other constitutional symptoms. Yet its use was limited by toxicity, leading to early treatment discontinuation in about 20% of the patients. However, its lack of leukemogenic potential and its possible use during pregnancy have already made IFN-alpha the drug of choice for younger MPN patients. In addition, several studies have shown a probably selective effect of IFN-alpha on PV and ET clones, as shown by cytogenetic remissions, reversions to polyclonal hematopoiesis, and more recently by induction of JAK2V617F complete molecular remissions in PV which may widen the indications of IFN-alpha in JAK2-mutated MPN.
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PMID:Interferon-alpha therapy in bcr-abl-negative myeloproliferative neoplasms. 1884 85

Primary myelofibrosis (PMF) is a clonal stem cell disorder that manifests clinically as anemia, splenomegaly due to extramedullary hematopoiesis, leukoerythroblastosis, and constitutional symptoms, which are the clinical hallmarks of PMF. Within the past three years it has been determined that a single, recurrent, somatic mutation in the gene encoding the cytoplasmic tyrosine kinase Janus kinase 2 (JAK2) occurs in the majority of patients with PMF, and more recently, activating mutations in the gene encoding the thrombopoietin receptor MPL have also been identified in a subset of PMF patients. These discoveries have yielded important insights into the pathogenesis of PMF and have brought about the first opportunity for rationally targeted therapy for this disorder. Here we present an updated review of the pathogenesis, definition, and treatment of PMF in light of the discovery of JAK2 and MPL mutations, as well as other recent work in the myeloproliferative neoplasm field.
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PMID:Primary myelofibrosis: update on definition, pathogenesis, and treatment. 1894 94

We measured histone deacetylase (HDAC) activity in 17 patients with primary myelofibrosis (PMF); 19 with other myeloproliferative neoplasm (MPN) and 16 normal volunteers. Significantly elevated HDAC levels were shown in patients with PMF compared with other MPN patients and normal volunteers (p<0.05). Sixteen patients with PMF were also studied for correlation between JAK2 mutation status and HDAC levels; no significant correlation was found. We further correlated HDAC levels with clinical features in PMF: there was no correlation with WBC, platelet counts, Hb levels or degree of bone marrow fibrosis, but HDAC levels were correlated to the degree of splenomegaly. This suggests that HDAC may be recruited as essential thrombocythemia or polycythemia vera progresses into myelofibrosis or PMF progresses into more advanced stage. We then used the qRT-PCR cycle threshold (CT) method to study which HDACs were elevated in PMF. The results showed that, in general, Class 1 HDACs were elevated (HDAC1,2,8) except HDAC3, Class II HDACs were depressed (HDAC4,5) except HDAC6 and 10, and Class III HDACs were generally elevated. The current study may form the basis for using HDAC inhibitor in the treatment of patients with PMF and may implicate a possible role of HDAC in the association of pathogenesis of PMF.
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PMID:Enhanced histone deacetylase enzyme activity in primary myelofibrosis. 1905 66


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