title: Myeloproliferative neoplasms can be initiated from a single hematopoietic stem cell expressing JAK2-V617F.
abstract: The majority of patients with myeloproliferative neoplasms (MPNs) carry a somatic JAK2-V617F mutation. Because additional mutations can precede JAK2-V617F, it is questioned whether JAK2-V617F alone can initiate MPN. Several mouse models have demonstrated that JAK2-V617F can cause MPN; however, in all these models disease was polyclonal. Conversely, cancer initiates at the single cell level, but attempts to recapitulate single-cell disease initiation in mice have thus far failed. We demonstrate by limiting dilution and single-cell transplantations that MPN disease, manifesting either as erythrocytosis or thrombocytosis, can be initiated clonally from a single cell carrying JAK2-V617F. However, only a subset of mice reconstituted from single hematopoietic stem cells (HSCs) displayed MPN phenotype. Expression of JAK2-V617F in HSCs promoted cell division and increased DNA damage. Higher JAK2-V617F expression correlated with a short-term HSC signature and increased myeloid bias in single-cell gene expression analyses. Lower JAK2-V617F expression in progenitor and stem cells was associated with the capacity to stably engraft in secondary recipients. Furthermore, long-term repopulating capacity was also present in a compartment with intermediate expression levels of lineage markers. Our studies demonstrate that MPN can be initiated from a single HSC and illustrate that JAK2-V617F has complex effects on HSC biology.
authors.affiliation: Department of Biomedicine, Experimental Hematology, University Hospital Basel and University of Basel, 4031 Basel, Switzerland.
authors.forename: Pontus
authors.initials: P
authors.lastname: Lundberg
authors.affiliation: Division of Hematology, University Hospital Zurich and University of Zurich, 8091 Zurich, Switzerland.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takizawa
authors.affiliation: Department of Biomedicine, Experimental Hematology, University Hospital Basel and University of Basel, 4031 Basel, Switzerland.
authors.forename: Lucia
authors.initials: L
authors.lastname: Kubovcakova
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, MA 02215.
authors.forename: Guoji
authors.initials: G
authors.lastname: Guo
authors.affiliation: Department of Biomedicine, Experimental Hematology, University Hospital Basel and University of Basel, 4031 Basel, Switzerland.
authors.forename: Hui
authors.initials: H
authors.lastname: Hao-Shen
authors.affiliation: Institute of Pathology, University Hospital Basel, 4031 Basel, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Dirnhofer
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, MA 02215.
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
authors.affiliation: Division of Hematology, University Hospital Zurich and University of Zurich, 8091 Zurich, Switzerland.
authors.forename: Markus G
authors.initials: MG
authors.lastname: Manz
authors.affiliation: Department of Biomedicine, Experimental Hematology, University Hospital Basel and University of Basel, 4031 Basel, Switzerland radek.skoda@unibas.ch.
authors.forename: Radek C
authors.initials: RC
authors.lastname: Skoda
mesh_terms: D000483:Alleles; D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D000954:Antigens, Surface / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002453:Cell Cycle / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D016000:Cluster Analysis; D004249:DNA Damage; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D016130:Immunophenotyping; D053614:Janus Kinase 2 / Q000235:genetics*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000235:genetics*; D010641:Phenotype; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D018183:Transplantation Chimera
chemical_list: D000950:Antigens, Ly; D000954:Antigens, Surface; D015415:Biomarkers; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D019009:Proto-Oncogene Proteins c-kit; D053614:Janus Kinase 2