title: Cooperation of germ line JAK2 mutations E846D and R1063H in hereditary erythrocytosis with megakaryocytic atypia.
abstract: The role of somatic JAK2 mutations in clonal myeloproliferative neoplasms (MPNs) is well established. Recently, germ line JAK2 mutations were associated with polyclonal hereditary thrombocytosis and triple-negative MPNs. We studied a patient who inherited 2 heterozygous JAK2 mutations, E846D from the mother and R1063H from the father, and exhibited erythrocytosis and megakaryocytic atypia but normal platelet number. Culture of erythroid progenitors from the patient and his parents revealed hypersensitivity to erythropoietin (EPO). Using cellular models, we show that both E846D and R1063H variants lead to constitutive signaling (albeit much weaker than JAK2 V617F), and both weakly hyperactivate JAK2/STAT5 signaling only in the specific context of the EPO receptor (EPOR). JAK2 E846D exhibited slightly stronger effects than JAK2 R1063H and caused prolonged EPO-induced phosphorylation of JAK2/STAT5 via EPOR. We propose that JAK2 E846D predominantly contributes to erythrocytosis, but is not sufficient for the full pathological phenotype to develop. JAK2 R1063H, with very weak effect on JAK2/STAT5 signaling, is necessary to augment JAK2 activity caused by E846D above a threshold level leading to erythrocytosis with megakaryocyte abnormalities. Both mutations were detected in the germ line of rare polycythemia vera, as well as certain leukemia patients, suggesting that they might predispose to hematological malignancy.
authors.affiliation: Department of Biology, Faculty of Medicine and Dentistry, Palacký University, Olomouc, Czech Republic; Signal Transduction and Molecular Hematology Unit, Ludwig Institute for Cancer Research, Brussels, Belgium; de Duve Institute, Université catholique de Louvain, Brussels, Belgium;
authors.forename: Katarina
authors.initials: K
authors.lastname: Kapralova
authors.affiliation: Department of Biology, Faculty of Medicine and Dentistry, Palacký University, Olomouc, Czech Republic;
authors.forename: Monika
authors.initials: M
authors.lastname: Horvathova
authors.affiliation: Signal Transduction and Molecular Hematology Unit, Ludwig Institute for Cancer Research, Brussels, Belgium; de Duve Institute, Université catholique de Louvain, Brussels, Belgium;
authors.forename: Christian
authors.initials: C
authors.lastname: Pecquet
authors.affiliation: Department of Biology, Faculty of Medicine and Dentistry, Palacký University, Olomouc, Czech Republic;
authors.forename: Jana
authors.identifier: 0000-0002-8808-9411
authors.initials: J
authors.lastname: Fialova Kucerova
authors.affiliation: Department of Pediatrics, University Hospital and Faculty of Medicine and Dentistry, Olomouc, Czech Republic; and.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Pospisilova
authors.affiliation: Signal Transduction and Molecular Hematology Unit, Ludwig Institute for Cancer Research, Brussels, Belgium; de Duve Institute, Université catholique de Louvain, Brussels, Belgium;
authors.forename: Emilie
authors.initials: E
authors.lastname: Leroy
authors.affiliation: Department of Biology, Faculty of Medicine and Dentistry, Palacký University, Olomouc, Czech Republic;
authors.forename: Barbora
authors.initials: B
authors.lastname: Kralova
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Jelena D
authors.identifier: 0000-0001-7420-3298
authors.initials: JD
authors.lastname: Milosevic Feenstra
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Schischlik
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Robert
authors.identifier: 0000-0002-6997-8539
authors.initials: R
authors.lastname: Kralovics
authors.affiliation: Signal Transduction and Molecular Hematology Unit, Ludwig Institute for Cancer Research, Brussels, Belgium; de Duve Institute, Université catholique de Louvain, Brussels, Belgium;
authors.forename: Stefan N
authors.initials: SN
authors.lastname: Constantinescu
authors.affiliation: Department of Biology, Faculty of Medicine and Dentistry, Palacký University, Olomouc, Czech Republic;
authors.forename: Vladimir
authors.initials: V
authors.lastname: Divoky
mesh_terms: D000293:Adolescent; D000328:Adult; D005260:Female; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D008297:Male; D008533:Megakaryocytes / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D010766:Phosphorylation; D011086:Polycythemia / Q000151:congenital* / Q000235:genetics; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D017467:Receptors, Erythropoietin; D050799:STAT5 Transcription Factor; C507924:JAK2 protein, human; D053614:Janus Kinase 2