title: JAK2V617F homozygosity drives a phenotypic switch in myeloproliferative neoplasms, but is insufficient to sustain disease.
abstract: Genomic regions of acquired uniparental disomy (UPD) are common in malignancy and frequently harbor mutated oncogenes. Homozygosity for such gain-of-function mutations is thought to modulate tumor phenotype, but direct evidence has been elusive. Polycythemia vera (PV) and essential thrombocythemia (ET), 2 subtypes of myeloproliferative neoplasms, are associated with an identical acquired JAK2V617F mutation but the mechanisms responsible for distinct clinical phenotypes remain unclear. We provide direct genetic evidence and demonstrate that homozygosity for human JAK2V617F in knock-in mice results in a striking phenotypic switch from an ET-like to PV-like phenotype. The resultant erythrocytosis is driven by increased numbers of early erythroid progenitors and enhanced erythroblast proliferation, whereas reduced platelet numbers are associated with impaired platelet survival. JAK2V617F-homozygous mice developed a severe hematopoietic stem cell defect, suggesting that additional lesions are needed to sustain clonal expansion. Together, our results indicate that UPD for 9p plays a causal role in the PV phenotype in patients as a consequence of JAK2V617F homozygosity. The generation of a JAK2V617F allelic series of mice with a dose-dependent effect on hematopoiesis provides a powerful model for studying the consequences of mutant JAK2 homozygosity.
authors.affiliation: Cambridge Institute for Medical Research and Wellcome Trust/Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom; Department of Haematology, University of Cambridge, United Kingdom;
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.affiliation: Cambridge Institute for Medical Research and Wellcome Trust/Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom; Department of Haematology, University of Cambridge, United Kingdom;
authors.forename: David G
authors.identifier: http://orcid.org/0000-0001-7871-8811
authors.initials: DG
authors.lastname: Kent
authors.affiliation: Cambridge Institute for Medical Research and Wellcome Trust/Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom; Department of Haematology, University of Cambridge, United Kingdom; Department of Haematology, Addenbrooke's Hospital, Cambridge, United Kingdom;
authors.forename: Anna L
authors.initials: AL
authors.lastname: Godfrey
authors.affiliation: Department of Haematology, University of Cambridge, United Kingdom; National Health Service Blood and Transplant, Cambridge, United Kingdom;
authors.forename: Harriet
authors.initials: H
authors.lastname: Manning
authors.affiliation: Cambridge Institute for Medical Research and Wellcome Trust/Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom; Department of Haematology, University of Cambridge, United Kingdom; Department of Haematology, Addenbrooke's Hospital, Cambridge, United Kingdom;
authors.forename: Jyoti
authors.initials: J
authors.lastname: Nangalia
authors.affiliation: Cambridge Institute for Medical Research and Wellcome Trust/Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom; Department of Haematology, University of Cambridge, United Kingdom;
authors.forename: Athar
authors.initials: A
authors.lastname: Aziz
authors.affiliation: Cambridge Institute for Medical Research and Wellcome Trust/Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom; Department of Haematology, University of Cambridge, United Kingdom;
authors.forename: Edwin
authors.initials: E
authors.lastname: Chen
authors.affiliation: Department of Surgery, University of Cambridge, Cambridge, United Kingdom; and.
authors.forename: Kourosh
authors.initials: K
authors.lastname: Saeb-Parsy
authors.affiliation: Cambridge Institute for Medical Research and Wellcome Trust/Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom; Department of Haematology, University of Cambridge, United Kingdom;
authors.forename: Juergen
authors.initials: J
authors.lastname: Fink
authors.affiliation: Cambridge Institute for Medical Research and Wellcome Trust/Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom; Department of Haematology, University of Cambridge, United Kingdom;
authors.forename: Rachel
authors.initials: R
authors.lastname: Sneade
authors.affiliation: Cambridge Institute for Medical Research and Wellcome Trust/Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom; Department of Haematology, University of Cambridge, United Kingdom;
authors.forename: Tina L
authors.initials: TL
authors.lastname: Hamilton
authors.affiliation: Cambridge Institute for Medical Research and Wellcome Trust/Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom; Department of Haematology, University of Cambridge, United Kingdom;
authors.forename: Dean C
authors.initials: DC
authors.lastname: Pask
authors.affiliation: Cambridge Institute for Medical Research and Wellcome Trust/Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom; Department of Haematology, University of Cambridge, United Kingdom;
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Silber
authors.affiliation: Cambridge Institute for Medical Research and Wellcome Trust/Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom; Department of Haematology, University of Cambridge, United Kingdom;
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Haematology, University of Cambridge, United Kingdom; Department of Haematology, Addenbrooke's Hospital, Cambridge, United Kingdom; National Health Service Blood and Transplant, Cambridge, United Kingdom;
authors.forename: Cedric
authors.initials: C
authors.lastname: Ghevaert
authors.affiliation: Welcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors.forename: Pentao
authors.initials: P
authors.lastname: Liu
authors.affiliation: Cambridge Institute for Medical Research and Wellcome Trust/Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom; Department of Haematology, University of Cambridge, United Kingdom; Department of Haematology, Addenbrooke's Hospital, Cambridge, United Kingdom;
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Green
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism / Q000473:pathology; D004900:Erythroblasts / Q000378:metabolism / Q000473:pathology; D005260:Female; D055879:Gene Knock-In Techniques; D006720:Homozygote; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D008297:Male; D008533:Megakaryocytes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D010641:Phenotype; D011087:Polycythemia Vera / Q000235:genetics* / Q000473:pathology; D013920:Thrombocythemia, Essential / Q000235:genetics* / Q000473:pathology; D024182:Uniparental Disomy / Q000235:genetics / Q000473:pathology
chemical_list: D053614:Janus Kinase 2