Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
J Exp Med. 2012 Mar 12;209(3):445-54. doi: 10.1084/jem.20111709. Epub 2012 Feb 20.
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.
多梳蛋白组 (PcG) 蛋白形成多蛋白多梳抑制复合物 (PRC) 1 和 2，并通过组蛋白修饰作为转录抑制剂发挥作用。它们通过抑制肿瘤抑制基因 Ink4a 和 Arf 的转录来维持造血干细胞和祖细胞的增殖能力，因此被认为是癌基因。然而，PcG 基因 EZH2 失活突变的鉴定揭示了其在髓系恶性肿瘤中的肿瘤抑制功能，包括原发性骨髓纤维化 (PMF)。在这里，我们表明另一个 PcG 基因 Bmi1 的缺失会导致类似于 PMF 的病理性造血。在小鼠模型中，Ink4a-Arf(-/-)造血细胞中 Bmi1 的缺失导致异常巨核细胞生成伴随着明显的骨髓外造血，最终导致致命性骨髓纤维化。Bmi1 的缺失导致一组基因的去抑制，包括在 PMF 中过表达的癌基因 Hmga2。染色质免疫沉淀分析显示 Bmi1 直接抑制 Hmga2 的转录。Hmga2 在造血干细胞中的过表达在小鼠中诱导了骨髓增生状态，并增强了巨核细胞生成，表明 Hmga2 在缺乏 Bmi1 的病理性造血发展中起作用。我们的研究结果提供了 Bmi1 肿瘤抑制功能的第一个遗传证据，并揭示了 PcG 蛋白通过沉默癌基因来限制生长的作用。
