title: Impact of isolated germline JAK2V617I mutation on human hematopoiesis.
abstract: The association between somatic JAK2 mutation and myeloproliferative neoplasms (MPNs) is now well established. However, because JAK2 mutations are associated with heterogeneous clinical phenotypes and often occur as secondary genetic events, some aspects of JAK2 mutation biology remain to be understood. We recently described a germline JAK2V617I mutation in a family with hereditary thrombocytosis and herein characterize the hematopoietic and signaling impact of JAK2V617I. Through targeted sequencing of MPN-associated mutations, exome sequencing, and clonality analysis, we demonstrate that JAK2V617I is likely to be the sole driver mutation in JAK2V617I-positive individuals with thrombocytosis. Phenotypic hematopoietic stem cells (HSCs) were increased in the blood and bone marrow of JAK2V617I-positive individuals and were sustained at higher levels than controls after xenotransplantation. In signaling and transcriptional assays, JAK2V617I demonstrated more activity than wild-type JAK2 but substantially less than JAK2V617F. After cytokine stimulation, JAK2V617I resulted in markedly increased downstream signaling compared with wild-type JAK2 and comparable with JAK2V617F. These findings demonstrate that JAK2V617I induces sufficient cytokine hyperresponsiveness in the absence of other molecular events to induce a homogeneous MPN-like phenotype. We also provide evidence that the JAK2V617I mutation may expand the HSC pool, providing insights into both JAK2 mutation biology and MPN disease pathogenesis.
authors.affiliation: Haematopoietic Stem Cell Biology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom. adam.mead@imm.ox.ac.uk
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Mead
authors.forename: Onima
authors.initials: O
authors.lastname: Chowdhury
authors.forename: Christian
authors.initials: C
authors.lastname: Pecquet
authors.forename: Alexandra
authors.initials: A
authors.lastname: Dusa
authors.forename: Petter
authors.initials: P
authors.lastname: Woll
authors.forename: Deborah
authors.initials: D
authors.lastname: Atkinson
authors.forename: Adam
authors.initials: A
authors.lastname: Burns
authors.forename: Joannah
authors.initials: J
authors.lastname: Score
authors.forename: Michelle
authors.initials: M
authors.lastname: Rugless
authors.forename: Ruth
authors.initials: R
authors.lastname: Clifford
authors.forename: Simon
authors.initials: S
authors.lastname: Moule
authors.forename: Nicola
authors.initials: N
authors.lastname: Bienz
authors.forename: Paresh
authors.initials: P
authors.lastname: Vyas
authors.forename: Nick
authors.initials: N
authors.lastname: Cross
authors.forename: Rosemary E
authors.initials: RE
authors.lastname: Gale
authors.forename: Shirley
authors.initials: S
authors.lastname: Henderson
authors.forename: Stefan N
authors.initials: SN
authors.lastname: Constantinescu
authors.forename: Anna
authors.initials: A
authors.lastname: Schuh
authors.forename: Sten Eirik W
authors.initials: SE
authors.lastname: Jacobsen
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D005190:Family; D005260:Female; D018095:Germ-Line Mutation / Q000502:physiology*; D006410:Hematopoiesis / Q000235:genetics* / Q000502:physiology; D006801:Humans; D007532:Isoleucine / Q000235:genetics; D053614:Janus Kinase 2 / Q000235:genetics*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D008875:Middle Aged; D009196:Myeloproliferative Disorders / Q000235:genetics / Q000503:physiopathology; D014633:Valine / Q000235:genetics
chemical_list: D007532:Isoleucine; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D014633:Valine