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Loss of <i>Ezh2</i> synergizes with <i>JAK2</i> -V617F in initiating myeloproliferative neoplasms and promoting myelofibrosis

Takafumi ShimizuExperimental Hematology, Department of Biomedicine, University Hospital Basel and University of Basel, 4031 Basel, Switzerland 1Lucia KubovčákováUniversity Hospital of BaselRonny NienholdExperimental Hematology, Department of Biomedicine, University Hospital Basel and University of Basel, 4031 Basel, Switzerland 1Jakub ZmajkovicExperimental Hematology, Department of Biomedicine, University Hospital Basel and University of Basel, 4031 Basel, Switzerland 1Sara C. MeyerExperimental Hematology, Department of Biomedicine, University Hospital Basel and University of Basel, 4031 Basel, Switzerland 1Hui Hao-ShenExperimental Hematology, Department of Biomedicine, University Hospital Basel and University of Basel, 4031 Basel, Switzerland 1Florian GeierBioinformatics Core Facility, Department of Biomedicine, University Hospital Basel, 4031 Basel, Switzerland 2Stephan DirnhoferInstitute of Pathology, University Hospital Basel, 4031 Basel, Switzerland 3Paola GuglielmelliDepartment of Clinical and Experimental Medicine, University of Florence, 50134 Florence, Italy 4Alessandro M. VannucchiDepartment of Clinical and Experimental Medicine, University of Florence, 50134 Florence, Italy 4Jelena D. Milosevic FeenstraCeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria 5Róbert KrálovicsCeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria 5Stuart H. OrkinDepartment of Pediatric Oncology, Dana Farber Cancer Institute, Boston, MA 02215 7Radek C. SkodaExperimental Hematology, Department of Biomedicine, University Hospital Basel and University of Basel, 4031 Basel, Switzerland 1

2016en

ABI

Annotatsiya

Myeloproliferative neoplasm (MPN) patients frequently show co-occurrence of JAK2-V617F and mutations in epigenetic regulator genes, including EZH2 In this study, we show that JAK2-V617F and loss of Ezh2 in hematopoietic cells contribute synergistically to the development of MPN. The MPN phenotype induced by JAK2-V617F was accentuated in JAK2-V617F;Ezh2(-/-) mice, resulting in very high platelet and neutrophil counts, more advanced myelofibrosis, and reduced survival. These mice also displayed expansion of the stem cell and progenitor cell compartments and a shift of differentiation toward megakaryopoiesis at the expense of erythropoiesis. Single cell limiting dilution transplantation with bone marrow from JAK2-V617F;Ezh2(+/-) mice showed increased reconstitution and MPN disease initiation potential compared with JAK2-V617F alone. RNA sequencing in Ezh2-deficient hematopoietic stem cells (HSCs) and megakaryocytic erythroid progenitors identified highly up-regulated genes, including Lin28b and Hmga2, and chromatin immunoprecipitation (ChIP)-quantitative PCR (qPCR) analysis of their promoters revealed decreased H3K27me3 deposition. Forced expression of Hmga2 resulted in increased chimerism and platelet counts in recipients of retrovirally transduced HSCs. JAK2-V617F-expressing mice treated with an Ezh2 inhibitor showed higher platelet counts than vehicle controls. Our data support the proposed tumor suppressor function of EZH2 in patients with MPN and call for caution when considering using Ezh2 inhibitors in MPN.

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DOI: 10.1084/jem.20151136

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