title: The JAK2 617V>F mutation triggers erythropoietin hypersensitivity and terminal erythroid amplification in primary cells from patients with polycythemia vera.
abstract: The JAK2 617V>F mutation is frequent in polycythemia vera (PV) and essential thrombocythemia (ET). Using quantitative polymerase chain reaction (PCR), we found that high levels of JAK2 617V>F in PV correlate with increased granulocytes and high levels of hemoglobin and endogenous erythroid colony formation. We detected normal progenitors and those that were heterozygous or homozygous for the mutation by genotyping ET and PV clonal immature and committed progenitors. In PV patients, we distinguished homozygous profiles with normal, heterozygous, and homozygous progenitors from heterozygous profiles with only heterozygous and normal progenitors. PV patients with a heterozygous profile had more mutated, committed progenitors than did other PV and ET patients, suggesting a selective amplification of mutated cells in the early phases of hematopoiesis. We demonstrated that mutated erythroid progenitors were more sensitive to erythropoietin than normal progenitors, and that most homozygous erythroid progenitors were erythropoietin independent. Moreover, we observed a greater in vitro erythroid amplification and a selective advantage in vivo for mutated cells in late stages of hematopoiesis. These results suggest that, for PV, erythrocytosis can occur through two mechanisms: terminal erythroid amplification triggered by JAK2 617V>F homozygosity, and a 2-step process including the upstream amplification of heterozygous cells that may involve additional molecular events.
authors: INSERM Unité 790, Universite Paris Sud, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France.
authors: Sabrina
authors: S
authors: Dupont
authors: Aline
authors: A
authors: Massé
authors: Chloé
authors: C
authors: James
authors: Irène
authors: I
authors: Teyssandier
authors: Yann
authors: Y
authors: Lécluse
authors: Frédéric
authors: F
authors: Larbret
authors: Valérie
authors: V
authors: Ugo
authors: Patrick
authors: P
authors: Saulnier
authors: Serge
authors: S
authors: Koscielny
authors: Jean Pierre
authors: JP
authors: Le Couédic
authors: Nicole
authors: N
authors: Casadevall
authors: William
authors: W
authors: Vainchenker
authors: François
authors: F
authors: Delhommeau
mesh_terms: D000368:Aged; D019943:Amino Acid Substitution; D002478:Cells, Cultured; D015672:Erythroid Precursor Cells / Q000378:metabolism* / Q000473:pathology; D004921:Erythropoietin / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D006098:Granulocytes / Q000378:metabolism / Q000473:pathology; D006410:Hematopoiesis / Q000187:drug effects*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D020125:Mutation, Missense; D011087:Polycythemia Vera / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013920:Thrombocythemia, Essential / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D004921:Erythropoietin; C507924:JAK2 protein, human; D053614:Janus Kinase 2