Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders

Baxter, E. Joanna; Scott, Linda M.; Campbell, Peter J.; East, Clare; Fourouclas, Nasios; Swanton, S; Vassiliou, George S.; Bench, Anthony J.; Boyd, Elaine; Curtin, Natasha Joan

doi:10.1016/s0140-6736(05)74230-6

Cited by 2,031 publications

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“…The discovery of a somatic mutation (V617F) in the tyrosine kinase, Janus Kinase 2 (JAK2) [1][2][3][4][5], was the most important advance in MPN since the discoveries 30 years ago that hematopoiesis in these disorders was both autonomous and clonal [6][7][8]. Although the murine models have provided unequivocal evidence that JAK2 V617F is able to cause MPNs, there is significant heterogeneity in disease phenotypes between different murine lines and even within the same line, suggesting that disease phenotype is affected by other unknown genetic or epigenetic factors [2,[9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

MicroRNA deregulation in polycythemia vera and essential thrombocythemia patients

Zhan

Cardozo

et al. 2013

Blood Cells, Molecules, and Diseases

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Polycythemia vera (PV) and essential thrombocythemia (ET) are the two most common myeloproliferative neoplasms. The same JAK2 V617F mutation can be found in both disorders and is able to recapitulate many of the phenotypic abnormalities of these diseases in the murine models. The disease phenotype is also influenced by other unknown genetic or epigenetic factors. MicroRNAs (miRNA) are 18-24 nucleotides single-stranded non-protein-coding RNAs that function primarily as gene repressors by binding to their target messenger RNAs. We performed miRNA expression profiling by oligonucleotide microarray analysis in purified peripheral blood CD34+ cells from eight JAK2 V617F -positive PV patients and six healthy donors. A quantitative reverse-transcription polymerase chain reaction assay was used to verify differential miRNA expression. Since erythrocytosis is the only feature that distinguishes PV from ET, we also compared specific miRNA expression in the nucleated erythroid cells directly descended from the early erythroid progenitor cells of PV and ET patients. Our data indicate that significant miRNA deregulation occurs in PV CD34+ cells and confirm a genetic basis for the gender-specific differences that characterize PV with respect to miRNA. The results of our study also suggest that deregulated miRNAs may represent an important mechanism by which the PV erythrocytosis and ET thrombocytosis phenotypes are determined.

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Section: Introductionmentioning

confidence: 99%

MicroRNA deregulation in polycythemia vera and essential thrombocythemia patients

Zhan

Cardozo

et al. 2013

Blood Cells, Molecules, and Diseases

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“…The Tel-JAK2 fusion protein found in acute lymphoblastic leukemias (ALL) with the t(9;12) translocation leads to the constitutive activation of JAK2 and STAT5 (Lacronique et al, 1997). Recently, an activating mutation in JAK2 (V617F) was found in the majority of patients with polycythemia vera and a significant proportion of patients with other myeloproliferative disorders such as essential thrombocythemia and idiopathic myelofibrosis (Baxter et al, 2005;James et al, 2005;Kralovics et al, 2005;Levine et al, 2005). When JAK2 V617F was transfected into factor-dependent cells, these cells became hypersensitive to cytokines and rapidly acquired cytokine independence, with constitutive activation of STAT5, the ERK/MAP kinase and the PI3/ AKT pathways.…”

Section: Introductionmentioning

confidence: 99%

JAK kinases overexpression promotes in vitro cell transformation

et al. 2007

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Constitutive activation of the JAK-STAT pathway is frequent in cancer and contributes to oncogenesis. Here, we took advantage of the Ba/F3 cell line, a murine proB cell line dependent on IL-3 for growth, to analyse mechanisms of constitutive STAT activation in vitro. Cytokineindependent and tumorigenic Ba/F3 cell lines were derived from a two-step selection process. Cells transfected with a defective IL-9 receptor acquire IL-9 responsiveness during a first step of selection, and progress after a second selection step to autonomously growing tumorigenic cells. Microarray analysis pointed to JAK1 overexpression as a key genetic event in this transformation. Overexpression of JAK1 not only increased the sensitivity to IL-9 but also allowed a second selection step toward cytokine-independent growth with constitutive STAT activation. This progression was dependent on a functional FERM and kinase JAK1 domain. Similar results were observed after JAK2, JAK3 and TYK2 overexpression. All autonomous cell lines showed an activation of STAT5, ERK1-2 and AKT but only TYK2-overexpressing cell lines showed a constitutive activation of STAT3. Thus, JAK overexpression can be considered as one of the oncogenic events leading to the constitutive activation of the JAK-STAT pathway.

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“…For example, the ability to form erythroid colonies in the absence of erythropoietin (endogenous erythroid colonies, EECs), overexpression of the PRV-1 mRNA and reduced expression of c-MPL, are detected only in a subset of ET patients [5][6][7][8]. Similarly, the recently described point mutation in the JAK2 kinase (JAK2 V617F ), is present in only around 50% of ET patients [9,10]. Because introduction of the JAK2 V617F mutation into a murine bone marrow transplantation model recapitulates many features of myeloproliferative disorders, including, in some cases, thrombocythemia, it appears intimately involved in the molecular etiology of disease development [11,12].…”

Section: Introductionmentioning

confidence: 99%

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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Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders

Cited by 2,031 publications

References 0 publications

MicroRNA deregulation in polycythemia vera and essential thrombocythemia patients

MicroRNA deregulation in polycythemia vera and essential thrombocythemia patients

JAK kinases overexpression promotes in vitro cell transformation

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

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