title: JAK2 and MPL protein levels determine TPO-induced megakaryocyte proliferation vs differentiation.
abstract: Megakaryopoiesis is a 2-step differentiation process, regulated by thrombopoietin (TPO), on binding to its cognate receptor myeloproliferative leukemia (MPL). This receptor associates with intracytoplasmic tyrosine kinases, essentially janus kinase 2 (JAK2), which regulates MPL stability and cell-surface expression, and mediates TPO-induced signal transduction. We demonstrate that JAK2 and MPL mediate TPO-induced proliferation arrest and megakaryocytic differentiation of the human megakaryoblastic leukemia cell line UT7-MPL. A decrease in JAK2 or MPL protein expression, and JAK2 chemical inhibition, suppress this antiproliferative action of TPO. The expression of JAK2 and MPL, which progressively increases along normal human megakaryopoiesis, is decreased in platelets of patients diagnosed with JAK2- or MPL-mutated essential thrombocytemia and primary myelofibrosis, 2 myeloproliferative neoplasms in which megakaryocytes (MKs) proliferate excessively. Finally, low doses of JAK2 chemical inhibitors are shown to induce a paradoxical increase in MK production, both in vitro and in vivo. We propose that JAK2 and MPL expression levels regulate megakaryocytic proliferation vs differentiation in both normal and pathological conditions, and that JAK2 chemical inhibitors could promote a paradoxical thrombocytosis when used at suboptimal doses.
authors.affiliation: INSERM Unité Mixte de Recherche 1009, Villejuif, France; Institut Gustave Roussy, Villejuif, France; Integrated Research Cancer Institute in Villejuif, Villejuif, France; Université Paris Diderot, Paris, France;
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Besancenot
authors.affiliation: INSERM Unité Mixte de Recherche 1009, Villejuif, France; Institut Gustave Roussy, Villejuif, France; Integrated Research Cancer Institute in Villejuif, Villejuif, France; Université Paris Diderot, Paris, France;
authors.forename: Damien
authors.initials: D
authors.lastname: Roos-Weil
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hématologie Biologique, Hôpital Henri-Mondor, Créteil, France; Faculty of Medicine, University Paris-12, Créteil, France;
authors.forename: Carole
authors.initials: C
authors.lastname: Tonetti
authors.affiliation: INSERM Unité Mixte de Recherche 1009, Villejuif, France; Institut Gustave Roussy, Villejuif, France; Integrated Research Cancer Institute in Villejuif, Villejuif, France; Université Paris Diderot, Paris, France;
authors.forename: Hadjer
authors.initials: H
authors.lastname: Abdelouahab
authors.affiliation: INSERM Unité Mixte de Recherche 1009, Villejuif, France; Institut Gustave Roussy, Villejuif, France; Integrated Research Cancer Institute in Villejuif, Villejuif, France; Faculty of Medicine, University Paris-Sud 11, Le Kremlin-Bicêtre, France;
authors.forename: Catherine
authors.initials: C
authors.lastname: Lacout
authors.affiliation: INSERM Unité Mixte de Recherche 1009, Villejuif, France; Institut Gustave Roussy, Villejuif, France; Integrated Research Cancer Institute in Villejuif, Villejuif, France; Université Paris Diderot, Paris, France;
authors.forename: Florence
authors.initials: F
authors.lastname: Pasquier
authors.affiliation: INSERM Unité Mixte de Recherche 1009, Villejuif, France; Institut Gustave Roussy, Villejuif, France; Integrated Research Cancer Institute in Villejuif, Villejuif, France; Université Paris Diderot, Paris, France;
authors.forename: Christophe
authors.initials: C
authors.lastname: Willekens
authors.affiliation: Institut Gustave Roussy, Villejuif, France;
authors.forename: Philippe
authors.initials: P
authors.lastname: Rameau
authors.affiliation: Institut Gustave Roussy, Villejuif, France;
authors.forename: Yann
authors.initials: Y
authors.lastname: Lecluse
authors.affiliation: INSERM Unité Mixte de Recherche 1009, Villejuif, France; Institut Gustave Roussy, Villejuif, France; Integrated Research Cancer Institute in Villejuif, Villejuif, France; Faculty of Medicine, University Paris-Sud 11, Le Kremlin-Bicêtre, France;
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Micol
authors.affiliation: Ludwig Institute for Cancer Research and de Duve Institute, Brussels, Belgium; and Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Stefan N
authors.initials: SN
authors.lastname: Constantinescu
authors.affiliation: INSERM Unité Mixte de Recherche 1009, Villejuif, France; Institut Gustave Roussy, Villejuif, France; Integrated Research Cancer Institute in Villejuif, Villejuif, France; Faculty of Medicine, University Paris-Sud 11, Le Kremlin-Bicêtre, France;
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
authors.affiliation: INSERM Unité Mixte de Recherche 1009, Villejuif, France; Institut Gustave Roussy, Villejuif, France; Integrated Research Cancer Institute in Villejuif, Villejuif, France; Faculty of Medicine, University Paris-Sud 11, Le Kremlin-Bicêtre, France;
authors.forename: Eric
authors.initials: E
authors.lastname: Solary
authors.affiliation: INSERM Unité Mixte de Recherche 1009, Villejuif, France; Integrated Research Cancer Institute in Villejuif, Villejuif, France; Assistance Publique-Hôpitaux de Paris, Hématologie Biologique, Hôpital Henri-Mondor, Créteil, France; Faculty of Medicine, University Paris-12, Créteil, France;
authors.forename: Stéphane
authors.initials: S
authors.lastname: Giraudier
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism*; D001792:Blood Platelets / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation; D015870:Gene Expression; D006801:Humans; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism*; D033862:Iron-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D008533:Megakaryocytes / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D010641:Phenotype; D055728:Primary Myelofibrosis / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D053628:Receptors, Thrombopoietin / Q000235:genetics / Q000378:metabolism*; D013920:Thrombocythemia, Essential / Q000235:genetics / Q000378:metabolism
chemical_list: D001324:Autoantigens; D033862:Iron-Binding Proteins; D034741:RNA, Small Interfering; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; C056658:TPO protein, human; D007453:Iodide Peroxidase; D053614:Janus Kinase 2