title: The loss of Ezh2 drives the pathogenesis of myelofibrosis and sensitizes tumor-initiating cells to bromodomain inhibition.
abstract: EZH2 is a component of polycomb repressive complex 2 (PRC2) and functions as an H3K27 methyltransferase. Loss-of-function mutations in EZH2 are associated with poorer outcomes in patients with myeloproliferative neoplasms (MPNs), particularly those with primary myelofibrosis (MF [PMF]). To determine how EZH2 insufficiency is involved in the pathogenesis of PMF, we generated mice compound for an Ezh2 conditional deletion and activating mutation in JAK2 (JAK2V617F) present in patients with PMF. The deletion of Ezh2 in JAK2(V617F) mice markedly promoted the development of MF, indicating a tumor suppressor function for EZH2 in PMF. The loss of Ezh2 in JAK2(V617F) hematopoietic cells caused significant reductions in H3K27 trimethylation (H3K27me3) levels, resulting in an epigenetic switch to H3K27 acetylation (H3K27ac). These epigenetic switches were closely associated with the activation of PRC2 target genes including Hmga2, an oncogene implicated in the pathogenesis of PMF. The treatment of JAK2(V617F)/Ezh2-null mice with a bromodomain inhibitor significantly attenuated H3K27ac levels at the promoter regions of PRC2 targets and down-regulated their expression, leading to the abrogation of MF-initiating cells. Therefore, an EZH2 insufficiency not only cooperated with active JAK2 to induce MF, but also conferred an oncogenic addiction to the H3K27ac modification in MF-initiating cells that was capable of being restored by bromodomain inhibition.
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan International Research Center for Medical Sciences, Kumamoto University, Chuo-ku, Kumamoto 860-0811, Japan sashidag@kumamoto-u.ac.jp aiwama@faculty.chiba-u.jp.
authors.forename: Goro
authors.identifier: 0000-0003-2318-5987
authors.initials: G
authors.lastname: Sashida
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan College of Life Sciences, Inner Mongolia University, Hohhot 010021, China.
authors.forename: Changshan
authors.identifier: 0000-0002-6719-2444
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Takahisa
authors.identifier: 0000-0002-7525-0851
authors.initials: T
authors.lastname: Tomioka
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Motohiko
authors.identifier: 0000-0002-3963-0013
authors.initials: M
authors.lastname: Oshima
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Kazumasa
authors.identifier: 0000-0002-2136-4562
authors.initials: K
authors.lastname: Aoyama
authors.affiliation: Department of Molecular Oncology and Leukemia Program Project, Research Institute for Radiation Biology and Medicine, Hiroshima University, Minami-ku, Hiroshima 734-8553, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Kanai
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Mochizuki-Kashio
authors.affiliation: Department of Hematology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Harada
authors.affiliation: Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Shimoda
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan sashidag@kumamoto-u.ac.jp aiwama@faculty.chiba-u.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwama
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000172:deficiency*; D025743:HMGA2 Protein / Q000096:biosynthesis / Q000235:genetics; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism; D055728:Primary Myelofibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D025743:HMGA2 Protein; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2