A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera.

  title={A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera.},
  author={Chlo{\'e} James and Val{\'e}rie Ugo and Jean Pierre Le Cou{\'e}dic and Judith Staerk and François Delhommeau and Catherine Lacout and Lo{\"i}c Garçon and Hana Raslova and Roland Berger and Annelise Bennaceur-Griscelli and Jean Luc Villeval and Stefan N. Constantinescu and Nicole Casadevall and William Vainchenker},
  volume={434 7037},
Myeloproliferative disorders are clonal haematopoietic stem cell malignancies characterized by independency or hypersensitivity of haematopoietic progenitors to numerous cytokines. The molecular basis of most myeloproliferative disorders is unknown. On the basis of the model of chronic myeloid leukaemia, it is expected that a constitutive tyrosine kinase activity could be at the origin of these diseases. Polycythaemia vera is an acquired myeloproliferative disorder, characterized by the… 

A unique activating mutation in JAK2 (V617F) is at the origin of polycythemia vera and allows a new classification of myeloproliferative diseases.

The identification of the JAK2 mutation represents a major advance in the understanding of the molecular pathogenesis of MPDs that will likely permit a new classification of these diseases and the development of novel therapeutic approaches.

New mutations and pathogenesis of myeloproliferative neoplasms.

Loss-of-function mutations in 3 genes involved in epigenetic regulation, TET2, ASXL1, and EZH2, may be early events preceding JAK2V617F but may also occur late during disease progression, and IZF1 deletions or TP53 mutations are mainly found at transformation phases and are present at greater frequency in de novo acute myeloid leukemias.

JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis.

Four somatic gain-of-function mutations affecting JAK2 exon 12 define a distinctive myeloproliferative syndrome that affects patients who currently receive a diagnosis of polycythemia vera or idiopathic erythrocytosis.

Aberrant signal transduction pathways in myeloproliferative neoplasms

Recent progress made in deciphering signaling anomalies in PV, ET and PMF is reviewed, with an emphasis on the relationship between JAK2 V617F and cytokine receptor signaling and on cross-talk with several other signaling pathways.

The genetic basis of myeloproliferative disorders.

  • R. Skoda
  • Biology, Medicine
    Hematology. American Society of Hematology. Education Program
  • 2007
The discovery of activating mutations in the Janus kinase 2 (JAK2) in most patients withMPD has fully transformed and energized the MPD field, and JAK2 now constitutes a prime target for developing specific inhibitors for the treatment of patients with MPD.

JAK-mutant myeloproliferative neoplasms.

  • R. Levine
  • Biology, Medicine
    Current topics in microbiology and immunology
  • 2012
This chapter will review the recent studies that identified genetic alterations that activate JAK signaling in different malignancies, and discuss the recent efforts aimed at developing small-molecule inhibitors of JAK kinase activity for the treatment of MPNs and other malignancy.

Polycythemia vera and essential thrombocythemia: new developments in biology with therapeutic implications.

PURPOSE OF REVIEW This review summarizes current understanding of the molecular genetics of polycythemia vera and essential thrombocythemia, with an emphasis on JAK2V617F pathophysiology and effect

The JAK2 mutation.

  • S. Merchant
  • Biology
    International review of cell and molecular biology
  • 2021

Myeloproliferative neoplasm induced by constitutive expression of JAK2V617F in knock-in mice.

Investigating the effect of an endogenous heterozygous expression of JAK2(V617F) in knock-in (KI) mice found that it results in severe PV-like disease with secondary myelofibrosis and not in ET- like disease as expected from patient study.



A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera

A clonal and recurrent mutation in the JH2 pseudo-kinase domain of the Janus kinase 2 (JAK2) gene in most (> 80%) polycythaemia vera patients leads to constitutive tyrosine phosphorylation activity that promotes cytokine hypersensitivity and induces erythrocytosis in a mouse model.

Identification of an Acquired JAK2 Mutation in Polycythemia Vera*

A gain-of-function mutation of JAK2 may explain the hypersensitivity of PV progenitor cells to growth factors and cytokines and is defined as a molecular defect of PV.

A gain-of-function mutation of JAK2 in myeloproliferative disorders.

Genetic evidence and in vitro functional studies indicate that V617F gives hematopoietic precursors proliferative and survival advantages and a high proportion of patients with myeloproliferative disorders carry a dominant gain-of-function mutation of JAK2.

The FIP1L1-PDGFRα fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: implications for diagnosis, classification, and management

The identification of a constitutively activated fusion tyrosine kinase on chromosome 4q12, derived from an interstitial deletion, that fuses the platelet-derived growth factor receptor-alpha gene (PDGFRA) to an uncharacterized human gene FIP1-like-1 (FIP1L1).

Tyrosine kinase fusion genes in chronic myeloproliferative diseases

Patients with PDGFRB or ABL fusion genes are candidates for treatment with Imatinib (STI571), but it is likely that alternative strategies will be necessary for the treatment of most other patients.

Imatinib targets other than bcr/abl and their clinical relevance in myeloid disorders.

The drug has now been shown to display equally impressive therapeutic activity in eosinophilia-associated chronic myeloproliferative disorders that are characterized by activating mutations of either the PDGFRB or the PDGFRA gene.

After chronic myelogenous leukemia: tyrosine kinase inhibitors in other hematologic malignancies.

This review focuses on tyrosine kinases that have been implicated in the pathogenesis of hematologic diseases other than chronic myelogenous leukemia and discusses the evidence for the use of small molecules to target these kinases.