Physiological Jak2V617F Expression Causes a Lethal Myeloproliferative Neoplasm with Differential Effects on Hematopoietic Stem and Progenitor Cells

• Published in: Cancer cell 2010-06, Vol.17 (6), p.584-596
• Main Authors: Mullally, Ann, Lane, Steven W., Ball, Brian, Megerdichian, Christine, Okabe, Rachel, Al-Shahrour, Fatima, Paktinat, Mahnaz, Haydu, J. Erika, Housman, Elizabeth, Lord, Allegra M., Wernig, Gerlinde, Kharas, Michael G., Mercher, Thomas, Kutok, Jeffery L., Gilliland, D. Gary, Ebert, Benjamin L.
• Format: Article
• Language: English
• Subjects: Amino Acid Substitution; Animals; Antigens, CD - metabolism; Bone Marrow - pathology; Bone Marrow Cells - drug effects; Bone Marrow Transplantation; Cell Count; Cell Differentiation - genetics; CELLCYCLE; Disease Models, Animal; Erythroid Precursor Cells - metabolism; Erythroid Precursor Cells - pathology; Erythropoietin - pharmacology; Gene Expression - genetics; Gene Expression Profiling; Hematocrit; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - pathology; Heterozygote; Humans; Janus Kinase 2 - antagonists & inhibitors; Janus Kinase 2 - genetics; Janus Kinase 2 - metabolism; Megakaryocyte Progenitor Cells - metabolism; Megakaryocyte Progenitor Cells - pathology; Megakaryocyte-Erythroid Progenitor Cells - drug effects; Megakaryocyte-Erythroid Progenitor Cells - metabolism; Megakaryocyte-Erythroid Progenitor Cells - pathology; Megakaryocyte-Erythroid Progenitor Cells - transplantation; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myeloid Progenitor Cells - metabolism; Myeloid Progenitor Cells - pathology; Myeloproliferative Disorders - drug therapy; Myeloproliferative Disorders - genetics; Myeloproliferative Disorders - pathology; Polycythemia Vera - genetics; Polycythemia Vera - pathology; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Pyrrolidines - pharmacology; Pyrrolidines - therapeutic use; Spleen - drug effects; Spleen - pathology; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; Survival Analysis
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccr.2010.05.015

We report a Jak2V617F knockin mouse myeloproliferative neoplasm (MPN) model resembling human polycythemia vera (PV). The MPN is serially transplantable and we demonstrate that the hematopoietic stem cell (HSC) compartment has the unique capacity for disease initiation but does not have a significant selective competitive advantage over wild-type HSCs. In contrast, myeloid progenitor populations are expanded and skewed toward the erythroid lineage, but cannot transplant the disease. Treatment with a JAK2 kinase inhibitor ameliorated the MPN phenotype, but did not eliminate the disease-initiating population. These findings provide insights into the consequences of JAK2 activation on HSC differentiation and function and have the potential to inform therapeutic approaches to JAK2V617F-positive MPN. ► Preclinical murine model of human PV in which MPN is serially transplantable ► Distinct cell populations responsible for disease initiation and MPN phenotype ► No significant selective competitive advantage for Jak2V617F-expressing HSCs ► Treatment with a JAK2 inhibitor did not eradicate MPN-initiating population