<i>JAK2</i>Exon 12 Mutations in Polycythemia Vera and Idiopathic Erythrocytosis

Scott, Linda M.; Tong, Wei; Levine, Ross L.; Scott, Mike; Beer, Philip; Stratton, Michael R.; Futreal, P. Andrew; Erber, Wendy N.; McMullin, Mary Frances; Harrison, Claire; Warren, Alan J.; Gilliland, D. Gary; Lodish, Harvey F.; Green, Anthony

doi:10.1056/nejmoa065202

Cited by 1,172 publications

(1,142 citation statements)

References 31 publications

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“…Unique mutations identified from this cohort are indicated by the asterisks. Mutations not described in this study are from Scott et al (10). MPL sequence variation associated with the chronic myeloproliferative disorders, K39N (25), S505N (26), W515K/L(11;12) as previously described.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic variations and new mutations in JAK2 V617F–negative polycythemia vera, erythrocytosis, and idiopathic myelofibrosis

Williams

Kim

Rogers

et al. 2007

Experimental Hematology

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Abstract(1) Objective-The chronic myeloproliferative disorders (MPD), polycythemia vera (PV), essential thrombocytosis (ET) and idiopathic myelofibrosis (IMF), are characterized by a spectrum of clinical features and linked by common genetic lesions in JAK2 and MPL. However, the clinical phenotypes in genetically undefined MPD patients are similar to those patients with JAK2 and MPL lesions. We, therefore, sought to determine whether there were JAK2 or MPL lesions in a welldefined, JAK2 V617F-negative MPD cohort, and to determine if clinical associations could be identified based on variations identified in these genes.(2) Methods-We examined the JAK2 and MPL genes in JAK2 V617F-negative PV, IMF and idiopathic erythrocytosis (ERT) patients for sequence variations.(3) Results-We identified two previously unrecognized JAK2 mutations and three previously unrecognized MPL mutations in JAK2 V617F-negative PV, erythrocytosis and IMF patients. We identified JAK2 exon 12 lesions in 30% of JAK2 V617F-negative PV patients, and either JAK2 V617F or JAK2 exon 12 lesions in 9% of ERT patients In IMF, in addition to the MPL gene mutation, W515K, we identified three additional mutations: 204P and 2 intervening sequence transitions: IVS 11/12 and 10/11.(4) Conclusions-While the clinical phenotype of JAK2 exon 12 lesions in the MPD was predominantly erythroid, there was significant disease spectrum overlap between JAK2 V617F and JAK2 exon 12 mutations. By contrast, MPL gene mutations were not associated with erythrocytosis, but segregated primarily with the phenotypes of thrombocytosis, extramedullary disease, myelofibrosis and osteosclerosis.

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Section: Discussionmentioning

confidence: 99%

Phenotypic variations and new mutations in JAK2 V617F–negative polycythemia vera, erythrocytosis, and idiopathic myelofibrosis

Williams

Kim

Rogers

et al. 2007

Experimental Hematology

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“…For those remaining 8 -10% of PV patients, as well as for the 50 % of ET patients, who do not carry the JAK2 V617F mutation, however, the molecular cause of disease evolutions remains unclear. Recent data from Scott et al, describing mutations in exon 12 of the JAK2 kinase in non-JAK2 V617F PV patients, raised the intriguing possibility that all MPDs arise from mutations within the JAK/STAT signaling pathway, albeit perhaps at different locations or in different proteins [13].…”

Section: Discussionmentioning

confidence: 99%

“…Scott et al recently described novel JAK2 mutations in JAK2 V617F -negative polycythemia vera (PV) patients [13]. Affected individuals carry a variety of alterations in exon 12, involving amino acids 538-543.…”

Section: Introductionmentioning

confidence: 99%

“…Affected individuals carry a variety of alterations in exon 12, involving amino acids 538-543. Similar to JAK2 V617F , exon 12 mutations result in a gain of function, cause constitutive STAT phosphorylation and evoke erythrocytosis and thrombocytosis in a mouse model [13]. Likewise, the c-Mpl W515L mutation, which can occur in isolation or in the context of the JAK2 V617F mutation, leads to constitutive JAK/STAT signaling [14][15][16].…”

Section: Introductionmentioning

confidence: 99%

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JAK2-negative ET patients do not display constitutively active JAK/STAT signaling

Schwemmers

Will

Waller

et al. 2007

Experimental Hematology

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Objective-Presence of the JAK2 V617F mutation in only 40-60% of patients with Essential Thrombocythemia (ET) underscores the heterogeneity of this myeloproliferative disorder (MPD). Several distinct mutations, either in JAK2 (exon 12) or in c-Mpl (W515L) have been described in subsets of other MPDs, Polycythemia vera (PV) and Idiopathic Myelofibrosis (IMF). Analogous to JAK2 V617F , these mutations cause constitutive JAK2 and STAT activation. It has therefore been proposed that constitutive activation of the JAK/STAT pathway underlies the molecular etiology of all MPDs. We investigated the alternative hypothesis that distinct alterations, separate from the JAK/ STAT signal transduction pathway, underlie a subset of JAK2 V617F -negative ET.Methods-cDNA microarrays and qRT-PCR were used to compare gene expression in 40 ET patients with and without the JAK2 V617F mutation.Results-Unsupervised clustering of gene expression patterns in ET patients revealed two distinct subclasses of patients. These subclasses differed in presence or absence of the JAK2 V617F mutation. Patients lacking the JAK2 V617F mutation displayed significantly lower expression of the JAK/STAT target genes Pim-1 and SOCS2. In addition, JAK2 V617F -negative patients showed lower levels of STAT3 phosphorylation.Conclusions-These data demonstrate that a large proportion of JAK2 V617F -negative ET patients do not display constitutive JAK/STAT signaling. Hence, we propose that alterations in different signal transduction pathways can lead to the clinical phenotype of ET. Elucidation of novel ETinducing changes will facilitate both a molecular classification of ET and the development of rationally designed therapies.

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“…The V617F mutation resides in the region of the JAK2 gene encoding the pseudokinase domain, which is thought to function as an autoinhibitory domain to regulate JAK2 tyrosine kinase activity. Mutations in exon 12 of JAK2, which also result in constitutive JAK2 kinase activity, are also observed with a lesser frequency (o5% in PV and ET) and are mutually exclusive with JAK2-V617F lesions (Pardanani et al, 2007;Scott et al, 2007). JAK2 is a member of a non-receptor tyrosine kinase family that also includes JAK1, TYK2 and JAK3 and functions as a mediator of cytokine receptor signaling (for review see Murray, 2007).…”

Section: Genetic Alterations Underlying Ph(à) Mpdmentioning

confidence: 99%

Kinase drug discovery approaches in chronic myeloproliferative disorders

Kumar¹,

Purandare

Lee

et al. 2009

Oncogene

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JAK2Exon 12 Mutations in Polycythemia Vera and Idiopathic Erythrocytosis

Abstract: JAK2 exon 12 mutations define a distinctive myeloproliferative syndrome that affects patients who currently receive a diagnosis of polycythemia vera or idiopathic erythrocytosis.

Cited by 1,172 publications

References 31 publications

Phenotypic variations and new mutations in JAK2 V617F–negative polycythemia vera, erythrocytosis, and idiopathic myelofibrosis

Phenotypic variations and new mutations in JAK2 V617F–negative polycythemia vera, erythrocytosis, and idiopathic myelofibrosis

JAK2-negative ET patients do not display constitutively active JAK/STAT signaling

Kinase drug discovery approaches in chronic myeloproliferative disorders

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