title: Myeloproliferative neoplasms: JAK2 signaling pathway as a central target for therapy.
abstract: The discovery of the JAK2V617F mutation followed by the discovery of other genetic abnormalities allowed important progress in the understanding of the pathogenesis and management of myeloproliferative neoplasms (MPN)s. Classical Breakpoint cluster region-Abelson (BCR-ABL)-negative neoplasms include 3 main disorders: essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). Genomic studies have shown that these disorders are more heterogeneous than previously thought with 3 main entities corresponding to different gene mutations: the JAK2 disorder, essentially due to JAK2V617F mutation, which includes nearly all PVs and a majority of ETs and PMFs with a continuum between these diseases and the myeloproliferative leukemia (MPL) and calreticulin (CALR) disorders, which include a fraction of ET and PMF. All of these mutations lead to a JAK2 constitutive activation. Murine models either with JAK2V617F or MPLW515L, but also with JAK2 or MPL germ line mutations found in hereditary thrombocytosis, have demonstrated that they are drivers of myeloproliferation. However, the myeloproliferative driver mutation is still unknown in approximately 15% of ET and PMF, but appears to also target the JAK/Signal Transducer and Activator of Transcription (STAT) pathway. However, other mutations in genes involved in epigenetics or splicing also can be present and can predate or follow mutations in signaling. They are involved either in clonal dominance or in phenotypic changes, more particularly in PMF. They can be associated with leukemic progression and might have an important prognostic value such as additional sex comb-like 1 mutations. Despite this heterogeneity, it is tempting to target JAK2 and its signaling for therapy. However in PMF, Adenosine Tri-Phosphate (ATP)-competitive JAK2 inhibitors have shown their interest, but also their important limitations. Thus, other approaches are required, which are discussed in this review.
authors.affiliation: INSERM 1009, Institut Gustave Roussy, Villejuif, France; Institut Gustave Roussy, Villejuif, France; Université Paris XI, Institut Gustave Roussy, Villejuif, France; Ligue Nationale contre le Cancer, équipe labellisée, Villejuif, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Pasquier
authors.affiliation: INSERM 1009, Institut Gustave Roussy, Villejuif, France; Institut Gustave Roussy, Villejuif, France; Université Paris XI, Institut Gustave Roussy, Villejuif, France; Ligue Nationale contre le Cancer, équipe labellisée, Villejuif, France.
authors.forename: Xenia
authors.initials: X
authors.lastname: Cabagnols
authors.affiliation: INSERM 1009, Institut Gustave Roussy, Villejuif, France; Institut Gustave Roussy, Villejuif, France; Université Paris XI, Institut Gustave Roussy, Villejuif, France; Ligue Nationale contre le Cancer, équipe labellisée, Villejuif, France.
authors.forename: Lise
authors.initials: L
authors.lastname: Secardin
authors.affiliation: INSERM 1009, Institut Gustave Roussy, Villejuif, France; Institut Gustave Roussy, Villejuif, France; Université Paris XI, Institut Gustave Roussy, Villejuif, France; Ligue Nationale contre le Cancer, équipe labellisée, Villejuif, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Plo
authors.affiliation: INSERM 1009, Institut Gustave Roussy, Villejuif, France; Institut Gustave Roussy, Villejuif, France; Université Paris XI, Institut Gustave Roussy, Villejuif, France; Ligue Nationale contre le Cancer, équipe labellisée, Villejuif, France. Electronic address: verpre@igr.fr.
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004789:Enzyme Activation; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D053614:Janus Kinase 2
keywords: Calreticulin; Clinical management; Inhibitors; MPL; Pathogenesis