期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 209, 期 3, 页码 445-454出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20111709
关键词
-
资金
- Global COE (Global Center for Education and Research in Immune System Regulation and Treatment) MEXT, Japan [21390289]
- Japan Science and Technology Corporation (JST)
- Takeda Science Foundation
- Astellas Foundation for Research on Metabolic Disorders
- Tokyo Biochemical Research Foundation
- Japanese Society for the Promotion of Science
- Grants-in-Aid for Scientific Research [23791071, 23249015, 23130502, 21390289] Funding Source: KAKEN
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 extra-medullary 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据