The JAK2V617F tyrosine kinase mutation in myeloproliferative disorders: Status report and immediate implications for disease classification and diagnosis

Ayalew Tefferi, D. Gary Gilliland

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Abstract

Janus kinase 2 (JAK2) is a cytoplasmic protein-tyrosine kinase that catalyzes the transfer of the γ-phosphate group of adenosine triphosphate to the hydroxyl groups of specific tyrosine residues in signal transduction molecules. JAK2 mediates signaling downstream of cytokine receptors after ligand-induced autophosphorylation of both receptor and enzyme. The main downstream effectors of JAK2 are a family of transcription factors known as signal transducers and activators of transcription (STAT) proteins. The myeloproliferative disorders (MPD), a subgroup of myeloid malignancies, are clonal stem cell diseases characterized by an expansion of morphologically mature granulocyte, erythrold, megakaryocyte, or monocyte lineage cells. Among the traditionally classified MPD, the disease-causing mutation has been delineated, thus far, for only chronic myeloid leukemia (ie, bcr/abl). In the past 3 months, 7 different studies have independently described a close association between an activating JAK2 mutation (JAK2V617F) and the classic bcr/abl-negative MPD (ie, polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia) as well as the less frequent occurrence of the same mutation in both atypical MPD and the myelodysplastic syndrome. The particular finding is consistent with previous observations that have implicated the JAK/STAT signal transduction pathway in the pathogenesis of bcr/abl-negative MPD, including the phenotype of growth factor independence and/or hypersensitivity. The current article summarizes this new information and discusses its implications for both classification and diagnosis of MPD.

Original languageEnglish (US)
Pages (from-to)947-958
Number of pages12
JournalMayo Clinic Proceedings
Volume80
Issue number7
StatePublished - 2005

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Myeloproliferative Disorders
Janus Kinase 2
Protein-Tyrosine Kinases
Mutation
Signal Transduction
STAT Transcription Factors
Essential Thrombocythemia
Polycythemia Vera
Primary Myelofibrosis
Cytokine Receptors
Megakaryocytes
Myelodysplastic Syndromes
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Transducers
Granulocytes
Hydroxyl Radical
Tyrosine
Monocytes
Intercellular Signaling Peptides and Proteins
Hypersensitivity

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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title = "The JAK2V617F tyrosine kinase mutation in myeloproliferative disorders: Status report and immediate implications for disease classification and diagnosis",
abstract = "Janus kinase 2 (JAK2) is a cytoplasmic protein-tyrosine kinase that catalyzes the transfer of the γ-phosphate group of adenosine triphosphate to the hydroxyl groups of specific tyrosine residues in signal transduction molecules. JAK2 mediates signaling downstream of cytokine receptors after ligand-induced autophosphorylation of both receptor and enzyme. The main downstream effectors of JAK2 are a family of transcription factors known as signal transducers and activators of transcription (STAT) proteins. The myeloproliferative disorders (MPD), a subgroup of myeloid malignancies, are clonal stem cell diseases characterized by an expansion of morphologically mature granulocyte, erythrold, megakaryocyte, or monocyte lineage cells. Among the traditionally classified MPD, the disease-causing mutation has been delineated, thus far, for only chronic myeloid leukemia (ie, bcr/abl). In the past 3 months, 7 different studies have independently described a close association between an activating JAK2 mutation (JAK2V617F) and the classic bcr/abl-negative MPD (ie, polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia) as well as the less frequent occurrence of the same mutation in both atypical MPD and the myelodysplastic syndrome. The particular finding is consistent with previous observations that have implicated the JAK/STAT signal transduction pathway in the pathogenesis of bcr/abl-negative MPD, including the phenotype of growth factor independence and/or hypersensitivity. The current article summarizes this new information and discusses its implications for both classification and diagnosis of MPD.",
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