Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms

Blood. 2017 Feb 9;129(6):667-679. doi: 10.1182/blood-2016-10-695940. Epub 2016 Dec 27.


The genetic landscape of classical myeloproliferative neoplasm (MPN) is in large part elucidated. The MPN-restricted driver mutations, including those in JAK2, calreticulin (CALR), and myeloproliferative leukemia virus (MPL), abnormally activate the cytokine receptor/JAK2 pathway and their downstream effectors, more particularly the STATs. The most frequent mutation, JAK2V617F, activates the 3 main myeloid cytokine receptors (erythropoietin receptor, granulocyte colony-stimulating factor receptor, and MPL) whereas CALR or MPL mutants are restricted to MPL activation. This explains why JAK2V617F is associated with polycythemia vera, essential thrombocythemia (ET), and primary myelofibrosis (PMF) whereas CALR and MPL mutants are found in ET and PMF. Other mutations in genes involved in epigenetic regulation, splicing, and signaling cooperate with the 3 MPN drivers and play a key role in the PMF pathogenesis. Mutations in epigenetic regulators TET2 and DNMT3A are involved in disease initiation and may precede the acquisition of JAK2V617F. Other mutations in epigenetic regulators such as EZH2 and ASXL1 also play a role in disease initiation and disease progression. Mutations in the splicing machinery are predominantly found in PMF and are implicated in the development of anemia or pancytopenia. Both heterogeneity of classical MPNs and prognosis are determined by a specific genomic landscape, that is, type of MPN driver mutations, association with other mutations, and their order of acquisition. However, factors other than somatic mutations play an important role in disease initiation as well as disease progression such as germ line predisposition, inflammation, and aging. Delineation of these environmental factors will be important to better understand the precise pathogenesis of MPN.

Publication types

  • Review

MeSH terms

  • Calreticulin / genetics
  • Calreticulin / metabolism
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Disease Progression
  • Enhancer of Zeste Homolog 2 Protein / genetics
  • Enhancer of Zeste Homolog 2 Protein / metabolism
  • Epigenesis, Genetic*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Janus Kinase 2 / genetics
  • Janus Kinase 2 / metabolism
  • Mutation*
  • Polycythemia Vera / genetics*
  • Polycythemia Vera / metabolism
  • Polycythemia Vera / physiopathology
  • Primary Myelofibrosis / genetics*
  • Primary Myelofibrosis / metabolism
  • Primary Myelofibrosis / physiopathology
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Receptors, Erythropoietin / genetics
  • Receptors, Erythropoietin / metabolism
  • Receptors, Granulocyte Colony-Stimulating Factor / genetics
  • Receptors, Granulocyte Colony-Stimulating Factor / metabolism
  • Receptors, Thrombopoietin / genetics
  • Receptors, Thrombopoietin / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • STAT Transcription Factors / genetics
  • STAT Transcription Factors / metabolism
  • Thrombocythemia, Essential / genetics*
  • Thrombocythemia, Essential / metabolism
  • Thrombocythemia, Essential / physiopathology


  • ASXL1 protein, human
  • CALR protein, human
  • Calreticulin
  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • Receptors, Erythropoietin
  • Receptors, Granulocyte Colony-Stimulating Factor
  • Receptors, Thrombopoietin
  • Repressor Proteins
  • STAT Transcription Factors
  • TET2 protein, human
  • MPL protein, human
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA methyltransferase 3A
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • JAK2 protein, human
  • Janus Kinase 2