Lethal myelofibrosis induced by Bmi1-deficient hematopoietic cells unveils a tumor suppressor function of the polycomb group genes.
Lethal myelofibrosis induced by Bmi1-deficient hematopoietic cells unveils a tumor suppressor function of the polycomb group genes.
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DOI：
10.1084/jem.20111709
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发表时间：
2012-03-12
期刊：
影响因子：
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通讯作者：
Iwama A
中科院分区：
文献类型：
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作者：
Oguro H;Yuan J;Tanaka S;Miyagi S;Mochizuki-Kashio M;Ichikawa H;Yamazaki S;Koseki H;Nakauchi H;Iwama A
多梳状基因Bmi 1在骨髓纤维化中的抑癌作用多梳组蛋白（Polycomb group，PcG）形成多蛋白多梳抑制复合物（polycomb repressive complex，PRC）1和2，通过组蛋白修饰发挥转录抑制因子的功能。它们通过抑制肿瘤抑制基因即Ink 4a和Arf的转录来维持造血干细胞和祖细胞的增殖能力，因此被表征为癌基因。然而，PcG基因EZH 2失活突变的鉴定揭示了骨髓恶性肿瘤（包括原发性骨髓纤维化（PMF））中的肿瘤抑制功能。在这里，我们表明，另一个PcG基因，Bmi 1的损失，导致病理性造血类似PMF。在小鼠模型中，Ink 4a-Arf −/−造血细胞中Bmi 1的缺失诱导异常巨核细胞生成，伴有明显的髓外造血，最终导致致命的骨髓纤维化。Bmi 1的缺失导致了一组基因的去抑制，包括Hmga 2，这是一种在PMF中过表达的癌基因。染色质免疫沉淀分析表明，Bmi 1直接抑制Hmga 2的转录。造血干细胞中Hmga 2的过表达可诱导小鼠骨髓增生状态，并增强巨核细胞生成，这表明Hmga 2在Bmi 1缺失的情况下参与了病理性造血的发展。我们的研究结果提供了Bmi 1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。
Polycomb group gene Bmi1 functions as a tumor suppressor in myelofibrosis. 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.