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Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders

Key Points

  • Acquisition of the constitutively active Janus kinase 2 (JAK2)V617F mutation occurs in almost all patients with polycythaemia vera (PV) and in a significant number of patients with essential thombocythaemia (ET) and primary myelofibrosis (PMF).

  • JAK2V617F is a constitutively active tyrosine kinase that activates signal transducer and activator of transcription (Stat), mitogen activated protein kinase (MAPK) and phosphotidylinositol 3-kinase (PI3K) signalling pathways, and transforms haematopoietic progenitors.

  • The identification of JAK2V617F has had a significant impact on the classification, diagnosis and prognosis of PV, ET and PMF.

  • Gain-of-function mutations in JAK2 exon 12 and in the thrombopoietin receptor are observed in some patients with JAK2V617F-negative myeloproliferative disorders (MPD), suggesting constitutive activation of JAK2 signalling is central to the pathogenesis of PV, ET and PMF.

  • The presence of a single disease allele in related, but clinically distinct MPD indicates that additional genetic events contribute to the pathogenesis of these disorders.

  • The discovery of JAK2V617F has led to the development of selective JAK2 inhibitors for the treatment of PV, ET and PMF.

Abstract

The myeloproliferative disorders polycythaemia vera (PV), essential thombocythaemia (ET), and primary myelofibrosis (PMF) are clonal disorders of multipotent haematopoietic progenitors. The genetic cause of these diseases was not known until 2005, when several independent groups demonstrated that most patients with PV, ET and PMF acquire a single point mutation in the cytoplasmic tyrosine kinase JAK2 (JAK2V617F). These discoveries have changed the landscape for diagnosis and classification of PV, ET and PMF, and show the ability of genomic technologies to identify new molecular targets in human malignancies with pathogenetic, diagnostic and therapeutic significance.

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Figure 1: Classification and molecular pathogenesis of the MPD.
Figure 2: Mechanism of activation of JAK2 kinase activity by mutations in the JAK2 signalling pathway.
Figure 3: Current model of the pathogenesis of PV, ET and PMF.

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Acknowledgements

The Gililand Laboratory is supported by the US National Institutes of Health, the Howard Hughes Medical institute, the Leukemia and Lymphoma Society, and the Doris Duke Charitable Foundation. The Gilliland and Tefferi Laboratories are supported in part by a grant from the Myeloproliferative Disorders Foundation. D.G.G. is an Investigator of the Howard Hughes Medical Institute, and a Doris Duke Charitable Foundation Distinguished Clinical Scientist Award recipient. R.L.L. is an American Society of Hematology Basic Research Fellow Award recipient, and a Doris Duke Charitable Foundation Clinical Scientist Development Award recipient.

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Correspondence to Ayalew Tefferi or D. Gary Gilliland.

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Glossary

Polycythaemia vera

(PV). Chronic blood disorder characterized by increased red blood cell count.

Thrombocythaemia

Increased platelet count.

Mastocytosis

Chronic blood disorder characterized by an increased number of mast cells.

Uniparental disomy

Homozygosity at a genetic locus caused by mitotic recombination and duplication of either the maternal or paternal allele.

Cytokine receptor scaffold

Intracellular component of cytokine receptors that engages Janus kinases and enables the activation of signal transduction.

Leucopaenia

Low white blood cell count.

Erythrocytosis

Increased red blood cell count.

Leukocytosis

Increased white blood cell count.

Forme fruste

An atypical, especially a mild or incomplete, form of a disease.

Haematocrit

Increase in the cellular fraction of peripheral blood, caused by an increased red blood cell count.

Reduced intensity conditioning

Bone marrow transplantation strategy using lower doses of chemotherapy and radiation to minimize toxicity.

Anagrelide

A drug used to decrease the number of platelets in the blood of patients who have a myeloproliferative disorder.

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Levine, R., Pardanani, A., Tefferi, A. et al. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer 7, 673–683 (2007). https://doi.org/10.1038/nrc2210

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