title: Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms.
abstract: The genetic landscape of classical myeloproliferative neoplasm (MPN) is in large part elucidated. The MPN-restricted driver mutations, including those inJAK2, 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) whereasCALRorMPLmutants are restricted to MPL activation. This explains whyJAK2V617F is associated with polycythemia vera, essential thrombocythemia (ET), and primary myelofibrosis (PMF) whereasCALRandMPLmutants 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 regulatorsTET2andDNMT3Aare involved in disease initiation and may precede the acquisition ofJAK2V617F. Other mutations in epigenetic regulators such asEZH2andASXL1also 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.
authors.affiliation: Unité Mixte de Recherche (UMR) 1170, INSERM, Villejuif, France.|Gustave Roussy, Villejuif, France.|Université Paris-Saclay, UMR 1170, Villejuif, France; and.
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
authors.affiliation: Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Robert
authors.identifier: 0000-0002-6997-8539
authors.initials: R
authors.lastname: Kralovics
mesh_terms: D037282:Calreticulin / Q000235:genetics / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D000090205:DNA Methyltransferase 3A; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D049308:Dioxygenases; D018450:Disease Progression; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D011087:Polycythemia Vera / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D055728:Primary Myelofibrosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D053628:Receptors, Thrombopoietin / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism; D013920:Thrombocythemia, Essential / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology
chemical_list: C473949:ASXL1 protein, human; C576483:CALR protein, human; D037282:Calreticulin; D004268:DNA-Binding Proteins; C000717967:DNMT3A protein, human; D011518:Proto-Oncogene Proteins; D017467:Receptors, Erythropoietin; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D053628:Receptors, Thrombopoietin; D012097:Repressor Proteins; D050791:STAT Transcription Factors; C082218:MPL protein, human; D049308:Dioxygenases; C541081:TET2 protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; C507924:JAK2 protein, human; D053614:Janus Kinase 2