モチヅキ　マキコ   Mochidzuki Makiko   望月　牧子    所属   医学部 医学科    職種   助教
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Lethal myelofibrosis induced by Bmi1-deficient hematopoietic cells unveils a tumor suppressor function of the polycomb group genes.
掲載誌名	正式名：The Journal of experimental medicine 略　 称：J Exp Med ISSNコード：15409538/00221007
掲載区分	国外
巻・号・頁	209(3),pp.445-54
著者・共著者	Oguro Hideyuki, Yuan Jin, Tanaka Satomi, Miyagi Satoru, Mochizuki-Kashio Makiko, Ichikawa Hitoshi, Yamazaki Satoshi, Koseki Haruhiko, Nakauchi Hiromitsu, Iwama Atsushi
発行年月	2012/03
概要	Polycomb-group (PcG) proteins form the multiprotein polycomb repressive complexes (PRC) 1 and 2, and function as transcriptional repressors through histone modifications. They maintain the proliferative capacity of hematopoietic stem and progenitor cells by repressing the transcription of tumor suppressor genes, namely Ink4a and Arf, and thus have been characterized as oncogenes. However, the identification of inactivating mutations in the PcG gene, EZH2, unveiled a tumor suppressor function in myeloid malignancies, including primary myelofibrosis (PMF). Here, we show that loss of another PcG gene, Bmi1, causes pathological hematopoiesis similar to PMF. In a mouse model, loss of Bmi1 in Ink4a-Arf(-/-) hematopoietic cells induced abnormal megakaryocytopoiesis accompanied by marked extramedullary hematopoiesis, which eventually resulted in lethal myelofibrosis. Absence of Bmi1 caused derepression of a cohort of genes, including Hmga2, which is an oncogene overexpressed in PMF. Chromatin immunoprecipitation assays revealed that Bmi1 directly represses the transcription of Hmga2. Overexpression of Hmga2 in hematopoietic stem cells induced a myeloproliferative state with enhanced megakaryocytopoiesis in mice, implicating Hmga2 in the development of pathological hematopoiesis in the absence of Bmi1. Our findings provide the first genetic evidence of a tumor suppressor function of Bmi1 and uncover the role of PcG proteins in restricting growth by silencing oncogenes.
DOI	10.1084/jem.20111709
PMID	22351929