Myeloproliferative neoplasms can be initiated from a single hematopoietic stem cell expressing JAK2-V617F

• Published in: The Journal of experimental medicine Vol. 211; no. 11; pp. 2213 - 2230
• Main Authors: Lundberg, Pontus, Takizawa, Hitoshi, Kubovcakova, Lucia, Guo, Guoji, Hao-Shen, Hui, Dirnhofer, Stephan, Orkin, Stuart H, Manz, Markus G, Skoda, Radek C
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 20.10.2014
• Subjects: Alleles; Animals; Antigens, Ly - metabolism; Antigens, Surface - metabolism; Biomarkers - metabolism; Bone Marrow Transplantation; Cell Cycle - genetics; Cell Lineage - genetics; Cell Transformation, Neoplastic - genetics; Cluster Analysis; DNA Damage; Female; Gene Expression; Gene Expression Profiling; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - pathology; Immunophenotyping; Janus Kinase 2 - genetics; Membrane Proteins - metabolism; Mice; Mice, Knockout; Mutation; Myeloproliferative Disorders - genetics; Phenotype; Proto-Oncogene Proteins c-kit - metabolism; Transplantation Chimera
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20131371

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.