title: JAK2 inhibition has different therapeutic effects according to myeloproliferative neoplasm development in mice.
abstract: JAK2 inhibition therapy is used to treat patients suffering from myeloproliferative neoplasms (MPN). Conflicting data on this therapy are reported possibly linked to the types of inhibitors or disease type. Therefore, we decided to compare in mice the effect of a JAK2 inhibitor, Fedratinib, in MPN models of increasing severity: polycythemia vera (PV), post-PV myelofibrosis (PPMF) and rapid post-essential thrombocythemia MF (PTMF). The models were generated through JAK2 activation by the JAK2(V617F) mutation or MPL constant stimulation. JAK2 inhibition induced a correction of splenomegaly, leucocytosis and microcytosis in all three MPN models. However, the effects on fibrosis, osteosclerosis, granulocytosis, erythropoiesis or platelet counts varied according to the disease severity stage. Strikingly, complete blockade of fibrosis and osteosclerosis was observed in the PPMF model, linked to correction of MK hyper/dysplasia, but not in the PTMF model, suggesting that MF development may also become JAK2-independent. Interestingly, we originally found a decreased in the JAK2(V617F) allele burden in progenitor cells from the spleen but not in other cell types. Overall, this study shows that JAK2 inhibition has different effects according to disease phenotypes and can (i) normalize platelet counts, (ii) prevent the development of marrow fibrosis/osteosclerosis at an early stage and (iii) reduce splenomegaly through blockage of stem cell mobilization in the spleen.
authors.affiliation: Inserm, U.1009, Institut Gustave Roussy (IGR), Université Paris XI, Villejuif, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Debeurme
authors.affiliation: Inserm, U.1009, Institut Gustave Roussy (IGR), Université Paris XI, Villejuif, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Lacout
authors.affiliation: iBV, CNRS UMR7277, INSERM U1091, Université Nice-Sophia Antipolis, Nice, France.
authors.forename: Claudine
authors.initials: C
authors.lastname: Moratal
authors.affiliation: Sanofi Oncology, Cambridge, MA, USA.
authors.forename: Rebecca G
authors.initials: RG
authors.lastname: Bagley
authors.affiliation: Inserm, U.1009, Institut Gustave Roussy (IGR), Université Paris XI, Villejuif, France.
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
authors.affiliation: Sanofi Oncology, Cambridge, MA, USA.
authors.forename: Francisco
authors.initials: F
authors.lastname: Adrian
authors.affiliation: Inserm, U.1009, Institut Gustave Roussy (IGR), Université Paris XI, Villejuif, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Villeval
mesh_terms: D000818:Animals; D018450:Disease Progression; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D051379:Mice; D010976:Platelet Count; D011087:Polycythemia Vera / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D055728:Primary Myelofibrosis / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011759:Pyrrolidines / Q000008:administration & dosage*; D013163:Splenomegaly / Q000188:drug therapy; D013449:Sulfonamides / Q000008:administration & dosage*; D013920:Thrombocythemia, Essential / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D000096926:Benzenesulfonamides
chemical_list: D053614:Janus Kinase 2; D047428:Protein Kinase Inhibitors; D011759:Pyrrolidines; D013449:Sulfonamides; C528327:fedratinib; D000096926:Benzenesulfonamides
keywords: JAK2 inhibitor; fibrosis; myeloproliferative neoplasms; preclinical murine models