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)

Managing patients with myelofibrosis (MF) (both those with primary myelofibrosis or having evolved from an antecedent polycythemia vera or essential thrombocythemia) present many challenges to the hematologist. MF patients suffer from a variable, but severe range of disease manifestations including massive splenomegaly, cytopenias, significant constitutional symptoms, possible transformation to blast phase and premature death. Cure is achievable through allogeneic stem cell transplantation; yet, this therapy is either inappropriate or not an option for most patients. Current available therapies are palliative, but can sometimes be of significant value to MF patients. The discovery of the JAK2-V617F mutation, and other pathogenetic insights into the pathophysiology of myeloproliferative neoplasms, has ushered in an era of potential new therapies for MF. Over a dozen JAK2 inhibitors are in development, with the leading compounds such as INCB018424, TG101348 and others showing promising early results particularly for control of disease associated splenomegaly and symptoms. Parallel trials with immunomodulatory therapy for MF associated anemia and stromal manifestations of the disease are continuing. The future may well see the approval of a range of agents for MF patients, with differing mechanisms of action, efficacy and toxicity profiles.
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PMID:Emerging drugs for the therapy of primary and post essential thrombocythemia, post polycythemia vera myelofibrosis. 1955 8

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

Activating JAK2 V617F mutation is present in many patients with chronic myeloproliferative neoplasms. We evaluated, retrospectively, clinical and laboratory data from 70 patients with BCR-ABL1 negative, JAK2 positive, chronic myeloproliferative disease. Quantity of the JAK2 mutant allele was tested for correlation with the clinical presentation, type of chronic myeloproliferative disease, hemoglobin level, white blood cell and platelet counts, spleen size, and/or cardiovascular complications. RealTime-PCR was used for amplification of DNA from marrow or peripheral blood. Polycythemia vera was more frequently diagnosed among patients with >or=50% mutational load than among those with <50% mutational load (71% vs 25%; p = 0.003). Patients with >or=50% mutational load had higher mean white blood cell count (18.6 billion/L vs 11.3 billion/L; p = 0.043). Essential thrombocythemia patients were more likely to have <50% mutational load (48% vs 7%; p = 0.005). Splenomegaly was more frequent in patients with >or=50% mutational load independent of the diagnosis (89% vs 48%; p = 0.03). Cardiovascular complications were reported in 50% of patients with >or=50% mutational load vs 21% of patients with <50% mutational load. JAK2 quantitation was highest in polycythemia vera followed by chronic myeloproliferative disease, unclassifiable, and essential thrombocythemia patients. JAK2 quantitation appears important in clinical evaluation. Mutational load appears to be helpful in stratification of patients into subgroups with different frequency of complications. Quantitation of JAK2 mutational load may be useful in evaluating response to therapy.
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PMID:Correlation of JAK2 V617F mutant allele quantitation with clinical presentation and type of chronic myeloproliferative neoplasm. 1988 Jul 61

The discovery of an activating tyrosine kinase mutation JAK2V617F in myeloproliferative neoplasms (MPNs), polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) has resulted in the development of JAK2 inhibitors, of which several are being evaluated in phase I/II clinical studies. It is important to recognize that because the V617F mutation is localized in a region outside the adenosine triphosphate (ATP)-binding pocket of JAK2 enzyme, ATP-competitive inhibitors of JAK2 kinase (like the current JAK2 inhibitors in the clinic) are not likely to discriminate between wild-type and mutant JAK2 enzymes. Therefore, JAK2 inhibitors, by virtue of their near equipotent activity against wild-type JAK2 that is important for normal hematopoiesis, may have adverse myelosuppression as an expected side effect, if administered at doses that aim to completely inhibit the mutant JAK2 enzyme. While they may prove to be effective in controlling hyperproliferation of hematopoietic cells in PV and ET, they may not be able to eliminate mutant clones. On the other hand, JAK inhibitors may have great therapeutic benefit by controlling the disease for patients with MPNs who suffer from debilitating signs (eg, splenomegaly) or constitutional symptoms (which presumably result from high levels of circulating cytokines that signal through JAK enzymes). Indeed, the primary clinical benefits observed so far in MF patients have been significant reduction is splenomegaly, elimination of debilitating disease-related symptoms, and weight gain. Most importantly, patients with and without the JAK2V617F mutation appear to benefit to the same extent. In this review we summarize current clinical experience with JAK2 inhibitors in MPNs.
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PMID:Therapeutic potential of JAK2 inhibitors. 2000 49

Constitutive JAK2 activation in hematopoietic cells by the JAK2V617F mutation recapitulates myeloproliferative neoplasm (MPN) phenotypes in mice, establishing JAK2 inhibition as a potential therapeutic strategy. Although most polycythemia vera patients carry the JAK2V617F mutation, half of those with essential thrombocythemia or primary myelofibrosis do not, suggesting alternative mechanisms for constitutive JAK-STAT signaling in MPNs. Most patients with primary myelofibrosis have elevated levels of JAK-dependent proinflammatory cytokines (eg, interleukin-6) consistent with our observation of JAK1 hyperactivation. Accordingly, we evaluated the effectiveness of selective JAK1/2 inhibition in experimental models relevant to MPNs and report on the effects of INCB018424, the first potent, selective, oral JAK1/JAK2 inhibitor to enter the clinic. INCB018424 inhibited interleukin-6 signaling (50% inhibitory concentration [IC(50)] = 281nM), and proliferation of JAK2V617F(+) Ba/F3 cells (IC(50) = 127nM). In primary cultures, INCB018424 preferentially suppressed erythroid progenitor colony formation from JAK2V617F(+) polycythemia vera patients (IC(50) = 67nM) versus healthy donors (IC(50) > 400nM). In a mouse model of JAK2V617F(+) MPN, oral INCB018424 markedly reduced splenomegaly and circulating levels of inflammatory cytokines, and preferentially eliminated neoplastic cells, resulting in significantly prolonged survival without myelosuppressive or immunosuppressive effects. Preliminary clinical results support these preclinical data and establish INCB018424 as a promising oral agent for the treatment of MPNs.
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PMID:Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. 2013 Feb 43

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 somatic point mutation (V617F) in the JAK2 tyrosine kinase was found in a majority of patients with polycythemia vera (PV), essential thrombocythemia, and primary myelofibrosis. However, contribution of the JAK2V617F mutation in these 3 clinically distinct myeloproliferative neoplasms (MPNs) remained unclear. To investigate the role of JAK2V617F in the pathogenesis of these MPNs, we generated an inducible Jak2V617F knock-in mouse, in which the expression of Jak2V617F is under control of the endogenous Jak2 promoter. Expression of heterozygous mouse Jak2V617F evoked all major features of human polycythemia vera (PV), which included marked increase in hemoglobin and hematocrit, increased red blood cells, leukocytosis, thrombocytosis, splenomegaly, reduced serum erythropoietin (Epo) levels and Epo-independent erythroid colonies. Homozygous Jak2V617F expression also resulted in a PV-like disease associated with significantly greater reticulocytosis, leukocytosis, neutrophilia and thrombocytosis, marked expansion of erythroid progenitors and Epo-independent erythroid colonies, larger spleen size, and accelerated bone marrow fibrosis compared with heterozygous Jak2V617F expression. Biochemical analyses revealed Jak2V617F gene dosage-dependent activation of Stat5, Akt, and Erk signaling pathways. Our conditional Jak2V617F knock-in mice provide an excellent model that can be used to further understand the molecular pathogenesis of MPNs and to identify additional genetic events that cooperate with Jak2V617F in different MPNs.
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PMID:Conditional expression of heterozygous or homozygous Jak2V617F from its endogenous promoter induces a polycythemia vera-like disease. 2019 48

Myelofibrosis (either primary or postpolycythemia vera/essential thrombocythemia) is a chronic and debilitating myeloproliferative neoplasm for which there is no well-accepted standard of care. Clinical manifestations of this disease (e.g., cytopenias, splenomegaly, bone marrow fibrosis) and constitutional symptoms (e.g., hypercatabolic state, fatigue, night sweats, fever) create significant treatment challenges. For example, progressive splenomegaly increases the risk for more serious clinical sequelae (e.g., portal hypertension, splenic infarction). Myelofibrosis arises from hematopoietic stem cells or early progenitor cells. However, the molecular mechanisms underlying its pathogenesis and clinical presentation are poorly understood, delaying the development of effective and targeted treatments. Recent studies have implicated mutations that directly or indirectly lead to the deregulated activation of Janus-activated kinase 2 (JAK2). Appreciation for the activation of JAK2 and the importance of increased levels of circulating proinflammatory cytokines in the pathogenesis and clinical manifestations of myelofibrosis has led to novel therapeutic agents targeting JAKs. This review will briefly discuss the origins of the JAK2 hypothesis, the clinical relevance of JAK2 mutations in myelofibrosis, and recent clinical progress in targeting JAKs as a therapeutic intervention for patients with this chronic and debilitating disease.
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PMID:Therapeutic potential of Janus-activated kinase-2 inhibitors for the management of myelofibrosis. 2021 35

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

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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