title: Germ-line JAK2 mutations in the kinase domain are responsible for hereditary thrombocytosis and are resistant to JAK2 and HSP90 inhibitors.
abstract: The main molecular basis of essential thrombocythemia and hereditary thrombocytosis is acquired, and germ-line-activating mutations affect the thrombopoietin signaling axis. We have identified 2 families with hereditary thrombocytosis presenting novel heterozygous germ-line mutations of JAK2. One family carries the JAK2 R867Q mutation located in the kinase domain, whereas the other presents 2 JAK2 mutations, S755R/R938Q, located in cis in both the pseudokinase and kinase domains. Expression of Janus kinase 2 (JAK2) R867Q and S755R/R938Q induced spontaneous growth of Ba/F3-thrombopoietin receptor (MPL) but not of Ba/F3-human receptor of erythropoietin cells. Interestingly, both Ba/F3-MPL cells expressing the mutants and platelets from patients displayed thrombopoietin-independent phosphorylation of signal transducer and activator of transcription 1. The JAK2 R867Q and S755R/R938Q proteins had significantly longer half-lives compared with JAK2 V617F. The longer half-lives correlated with increased binding to the heat shock protein 90 (HSP90) chaperone and with higher MPL cell-surface expression. Moreover, these mutants were less sensitive to JAK2 and HSP90 inhibitors than JAK2 V617F. Our results suggest that the mutations in the kinase domain of JAK2 may confer a weak activation of signaling specifically dependent on MPL while inducing a decreased sensitivity to clinically available JAK2 inhibitors.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1009, Laboratory of Excellence GR-Ex, Villejuif, France;
authors.forename: Caroline
authors.initials: C
authors.lastname: Marty
authors.forename: Cécile
authors.initials: C
authors.lastname: Saint-Martin
authors.forename: Christian
authors.initials: C
authors.lastname: Pecquet
authors.forename: Sarah
authors.initials: S
authors.lastname: Grosjean
authors.forename: Joseph
authors.initials: J
authors.lastname: Saliba
authors.forename: Céline
authors.initials: C
authors.lastname: Mouton
authors.forename: Emilie
authors.initials: E
authors.lastname: Leroy
authors.forename: Ashot S
authors.initials: AS
authors.lastname: Harutyunyan
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Abgrall
authors.forename: Rémi
authors.initials: R
authors.lastname: Favier
authors.forename: Aurélie
authors.initials: A
authors.lastname: Toussaint
authors.forename: Eric
authors.initials: E
authors.lastname: Solary
authors.forename: Robert
authors.initials: R
authors.lastname: Kralovics
authors.forename: Stefan N
authors.initials: SN
authors.lastname: Constantinescu
authors.forename: Albert
authors.initials: A
authors.lastname: Najman
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
authors.forename: Isabelle
authors.initials: I
authors.lastname: Plo
authors.forename: Christine
authors.initials: C
authors.lastname: Bellanné-Chantelot
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D002478:Cells, Cultured; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D018095:Germ-Line Mutation; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics*; D008297:Male; D051379:Mice; D008875:Middle Aged; D010375:Pedigree; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D017434:Protein Structure, Tertiary / Q000235:genetics; D013922:Thrombocytosis / Q000188:drug therapy* / Q000235:genetics*; D055815:Young Adult
chemical_list: D018841:HSP90 Heat-Shock Proteins; D047428:Protein Kinase Inhibitors; C507924:JAK2 protein, human; D053614:Janus Kinase 2