JAK2 in Myeloproliferative Disorders Is Not Just Another Kinase

Tefferi, Ayalew; Gilliland, D. Gary

doi:10.4161/cc.4.8.1872

Cited by 60 publications

(39 citation statements)

References 50 publications

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“…12 A Val-to-Phe point mutation at position 617 of JAK2 (JAK2V617F) was identified in the majority patients with neoplastic myeloproliferative disorders. 13,14 Distinct hallmarks of tumor cells with the V617F mutation include cytokineindependent growth and hyper-responsiveness to many cytokines here is consistent with that measured by the three-dimensional stochastic optical reconstruction microscopy. 32 Further analysis revealed that some surface GMRβ clusters were co-localized with CHC (Fig.…”

Section: Introductionsupporting

confidence: 83%

Identification of a novel function of the clathrin-coated structure at the plasma membrane in facilitating GM-CSF receptor-mediated activation of JAK2

et al. 2012

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Section: Introductionsupporting

confidence: 83%

Identification of a novel function of the clathrin-coated structure at the plasma membrane in facilitating GM-CSF receptor-mediated activation of JAK2

et al. 2012

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“…The acquired JAK2 gene mutation on chromosome 9 (JAK2 V617F) is associated with polycythemia vera (PV) and other related MPNs (8). The reported prevalence of the JAK2 mutation has ranged from 65%-97% in PV patients from Europe and North America, 23%-57% in patients with essential thrombocythemia (ET), and 35%-57% in primary myelofibrosis (PMF) patients (8)(9)(10)(11)(12)(13)(14). The contributions of JAK2 mutation to MPN pathogenesis, disease phenotype, leukemic transformation, and stem cell involvement are unclear at present (15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Diagnostic value of the JAK2 V617F mutation for latent chronic myeloproliferative disorders in patients with budd-chiari syndrome and/or portal vein thrombosis

Karakose

Oruç²,

Zengin³

et al. 2015

Turk J Gastroenterol

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Background/Aims: The diagnosis of an underlying myeloproliferative neoplasm (MPN) is often problematic in patients with Budd Chiari syndrome (BCS) or portal vein thrombosis (PVT). This study aimed to assess the diagnostic value of the JAK2 gene V617F gain-of-function mutation for MPN in splanchnic vein thrombosis patients. Materials and Methods: One hundred eleven patients (80 with PVT, 27 with BCS, and 4 with BCS and PVT) were investigated. The control group included 56 volunteers without any known diseases. LightCycler SNP genotyping was performed to detect the JAK2 V617F mutation in DNA extracted from peripheral blood. Results: The JAK2 V617F mutation was identified in six of 28 patients (21.4%) with idiopathic PVT or BCS and in eight of 45 patients (17.8%) with PVT or BCS secondary to a known prothrombotic factor, but in only one of 38 patients (2.6%) with PVT and cirrhosis (p=0.049). Conclusion: The JAK2 V617F mutation is a noninvasive molecular marker for occult MPNs and can be used for the diagnosis of latent MPNs presenting with thrombotic events. Analysis of JAK2 mutation in the patients with idiopathic PVT or BCS showed that 20% had latent MPNs. In addition to this JAK2 mutation, prothrombotic events were observed in a significant number of patients with splanchnic vein thrombosis. JAK2 gene analysis should be included in the research panel for BCS and PVT patients without cirrhosis.

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“…For the first time, there is a molecular understanding of the underlying disease mechanism and, equally of importance, the mutated JAK2 is a druggable target for therapeutic intervention (4,5). The JAK2 valine 617 to phenylalanine mutation is found in nearly every patient with polycythemia vera (PV) as well as in approximately every second patient suffering from essential thrombocythemia and primary myelofibrosis (6). Interestingly, in the remainder of V617F-negative PV patients, mutations were discovered in JAK2 exon 12, also affecting the pseudokinase domain (7).…”

Section: Introductionmentioning

confidence: 99%

Potent and Selective Inhibition of Polycythemia by the Quinoxaline JAK2 Inhibitor NVP-BSK805

Baffert

Régnier²,

Pover³

et al. 2010

Molecular Cancer Therapeutics

109

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The recent discovery of an acquired activating point mutation in JAK2, substituting valine at amino acid position 617 for phenylalanine, has greatly improved our understanding of the molecular mechanism underlying chronic myeloproliferative neoplasms. Strikingly, the JAK2 V617F mutation is found in nearly all patients suffering from polycythemia vera and in roughly every second patient suffering from essential thrombocythemia and primary myelofibrosis. Thus, JAK2 represents a promising target for the treatment of myeloproliferative neoplasms and considerable efforts are ongoing to discover and develop inhibitors of the kinase. Here, we report potent inhibition of JAK2 V617F and JAK2 wild-type enzymes by a novel substituted quinoxaline, NVP-BSK805, which acts in an ATP-competitive manner. Within the JAK family, NVP-BSK805 displays more than 20-fold selectivity towards JAK2 in vitro, as well as excellent selectivity in broader kinase profiling. The compound blunts constitutive STAT5 phosphorylation in JAK2 V617F-bearing cells, with concomitant suppression of cell proliferation and induction of apoptosis. In vivo, NVP-BSK805 exhibited good oral bioavailability and a long half-life. The inhibitor was efficacious in suppressing leukemic cell spreading and splenomegaly in a Ba/F3 JAK2 V617F cell-driven mouse mechanistic model. Furthermore, NVP-BSK805 potently suppressed recombinant human erythropoietin-induced polycythemia and extramedullary erythropoiesis in mice and rats. Mol Cancer Ther; 9(7); 1945-55. ©2010 AACR.

show abstract

JAK2 in Myeloproliferative Disorders Is Not Just Another Kinase

Cited by 60 publications

References 50 publications

Identification of a novel function of the clathrin-coated structure at the plasma membrane in facilitating GM-CSF receptor-mediated activation of JAK2

Identification of a novel function of the clathrin-coated structure at the plasma membrane in facilitating GM-CSF receptor-mediated activation of JAK2

Diagnostic value of the JAK2 V617F mutation for latent chronic myeloproliferative disorders in patients with budd-chiari syndrome and/or portal vein thrombosis

Potent and Selective Inhibition of Polycythemia by the Quinoxaline JAK2 Inhibitor NVP-BSK805

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