title: Thrombopoietin receptor down-modulation by JAK2 V617F: restoration of receptor levels by inhibitors of pathologic JAK2 signaling and of proteasomes.
abstract: The constitutively active JAK2 V617F mutant is the major determinant of human myeloproliferative neoplasms (MPNs). We show that coexpression of murine JAK2 V617F and the murine thrombopoietin (Tpo) receptor (TpoR, c-MPL) in hematopoietic cell lines or heterozygous knock-in of JAK2 V617F in mice leads to down-modulation of TpoR levels. Enhanced TpoR ubiquitinylation, proteasomal degradation, reduced recycling, and maturation are induced by the constitutive JAK2 V617F activity. These effects can be prevented in cell lines by JAK2 and proteasome inhibitors. Restoration of TpoR levels by inhibitors could be detected in platelets from JAK2 inhibitor-treated myelofibrosis patients that express the JAK2 V617F mutant, and in platelets from JAK2 V617F knock-in mice that were treated in vivo with JAK2 or proteasome inhibitors. In addition, we show that Tpo can induce both proliferative and antiproliferative effects via TpoR at low and high JAK2 activation levels, respectively, or on expression of JAK2 V617F. The antiproliferative signaling and receptor down-modulation by JAK2 V617F were dependent on signaling via TpoR cytosolic tyrosine 626. We propose that selection against TpoR antiproliferative signaling occurs by TpoR down-modulation and that restoration of down-modulated TpoR levels could become a biomarker for the treatment of MPNs.
authors.affiliation: Ludwig Institute for Cancer Research, Brussels, Belgium.
authors.forename: Christian
authors.initials: C
authors.lastname: Pecquet
authors.forename: Carmen C
authors.initials: CC
authors.lastname: Diaconu
authors.forename: Judith
authors.initials: J
authors.lastname: Staerk
authors.forename: Michael
authors.initials: M
authors.lastname: Girardot
authors.forename: Caroline
authors.initials: C
authors.lastname: Marty
authors.forename: Yohan
authors.initials: Y
authors.lastname: Royer
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Defour
authors.forename: Alexandra
authors.initials: A
authors.lastname: Dusa
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Besancenot
authors.forename: Stephane
authors.initials: S
authors.lastname: Giraudier
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Villeval
authors.forename: Laurent
authors.initials: L
authors.lastname: Knoops
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Courtoy
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
authors.forename: Stefan N
authors.initials: SN
authors.lastname: Constantinescu
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics / Q000502:physiology; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D057809:HEK293 Cells; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020125:Mutation, Missense / Q000502:physiology; D010649:Phenylalanine / Q000235:genetics; D061988:Proteasome Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D020239:Receptor Cross-Talk / Q000187:drug effects / Q000502:physiology; D053628:Receptors, Thrombopoietin / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014633:Valine / Q000235:genetics
chemical_list: D061988:Proteasome Inhibitors; D047428:Protein Kinase Inhibitors; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; D010649:Phenylalanine; D053614:Janus Kinase 2; D014633:Valine