A Gain-of-Function Mutation of<i>JAK2</i>in Myeloproliferative Disorders

Královics, Róbert; Passamonti, Francesco; Buser, Andreas; Teo, Soon Siong; Tiedt, Ralph; Passweg, Jakob; Thewis, André; Cazzola, Mario; Skoda, Radek C.

doi:10.1056/nejmoa051113

Cited by 3,216 publications

(2,740 citation statements)

References 44 publications

Supporting

Mentioning

2,591

Contrasting

Unclassified

Order By: Relevance

“…Since SOCS-1 was found to be hypermethylated and thereby silenced in several types of lymphomas (Chen et al, 2003;Galm et al, 2003;Chim et al, 2004a, b), it is tempting to speculate that the two cHL cases without mutations of the SOCS-1 gene but detectable phospho-STAT5 might have downregulated SOCS-1 expression due to aberrant DNA methylation or other mutations that constitutively activate STAT5. Recently, constitutive kinase activity due to the gain of function mutation V617F in JAK2 has been shown to increase phospho-STAT5 level by ectopic expression of the V617F JAK2 variant in BaF/3 cells and was frequently found in myeloproliferative disorders (James et al, 2005;Kralovics et al, 2005). Therefore, we checked DNA of the HL lines and the PMBL lines MedB-1 and Karpas1106 by site-specific restriction analysis for presence of the underlying G to T transversion but did not find this nucleotid exchange (Figure 4), indicating that this crucial sequence of JAK2 is wt in our HL and PMBL cell lines.…”

Section: For Figure Please Refer To Page 2681mentioning

confidence: 99%

Mutations of the tumor suppressor gene SOCS-1 in classical Hodgkin lymphoma are frequent and associated with nuclear phospho-STAT5 accumulation

et al. 2006

View full text Add to dashboard Cite

The suppressors of cytokine signaling (SOCS) are critically involved in the regulation of cellular proliferation, survival, and apoptosis via cytokine-induced JAK/ STAT signaling. SOCS-1 silencing by aberrant DNA methylation contributes to oncogenesis in various B-cell neoplasias and carcinomas. Recently, we showed an alternative loss of SOCS-1 function due to deleterious SOCS-1 mutations in a major subset of primary mediastinal B-cell lymphoma (PMBL) and in the PMBL line MedB-1, and a biallelic SOCS-1 deletion in PMBL line Karpas1106P. For both cell lines our previous data demonstrated retarded JAK2 degradation and sustained phospho-JAK2 action leading to enhanced DNA binding of phospho-STAT5. Here, we analysed SOCS-1 in lasermicrodissected Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL). We detected SOCS-1 mutations in HRS cells of eight of 19 cHL samples and in three of five Hodgkin lymphoma (HL)-derived cell lines by sequencing analysis. Moreover, we found a significant association between mutated SOCS-1 of isolated HRS cells and nuclear phospho-STAT5 accumulation in HRS cells of cHL tumor tissue (Po0.01). Collectively, these findings support the concept that PMBL and cHL share many overlapping features, and that defective tumor suppressor gene SOCS-1 triggers an oncogenic pathway operative in both lymphomas.

show abstract

Section: For Figure Please Refer To Page 2681mentioning

confidence: 99%

Mutations of the tumor suppressor gene SOCS-1 in classical Hodgkin lymphoma are frequent and associated with nuclear phospho-STAT5 accumulation

et al. 2006

View full text Add to dashboard Cite

show abstract

“…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

View full text Add to dashboard Cite

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.

show abstract

“…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

View full text Add to dashboard Cite

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.

show abstract

A Gain-of-Function Mutation ofJAK2in Myeloproliferative Disorders

Abstract: A high proportion of patients with myeloproliferative disorders carry a dominant gain-of-function mutation of JAK2.

Cited by 3,216 publications

References 44 publications

Mutations of the tumor suppressor gene SOCS-1 in classical Hodgkin lymphoma are frequent and associated with nuclear phospho-STAT5 accumulation

Mutations of the tumor suppressor gene SOCS-1 in classical Hodgkin lymphoma are frequent and associated with nuclear phospho-STAT5 accumulation

MicroRNA deregulation in polycythemia vera and essential thrombocythemia patients

JAK kinases overexpression promotes in vitro cell transformation

Contact Info

Product

Resources

About