title: Lethal myelofibrosis induced by Bmi1-deficient hematopoietic cells unveils a tumor suppressor function of the polycomb group genes.
abstract: 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.
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Oguro
authors.forename: Jin
authors.initials: J
authors.lastname: Yuan
authors.forename: Satomi
authors.initials: S
authors.lastname: Tanaka
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyagi
authors.forename: Makiko
authors.initials: M
authors.lastname: Mochizuki-Kashio
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ichikawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamazaki
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Nakauchi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwama
mesh_terms: D000818:Animals; D001483:Base Sequence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D016147:Genes, Tumor Suppressor; D025743:HMGA2 Protein / Q000235:genetics; D006411:Hematopoiesis, Extramedullary / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics*; D063150:Polycomb Repressive Complex 1; D063146:Polycomb-Group Proteins; D055728:Primary Myelofibrosis / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000235:genetics*; D012097:Repressor Proteins / Q000172:deficiency* / Q000235:genetics*; D034061:Thrombopoiesis / Q000235:genetics
chemical_list: C489421:Bmi1 protein, mouse; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D017931:DNA Primers; D025743:HMGA2 Protein; D009687:Nuclear Proteins; D063146:Polycomb-Group Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D063150:Polycomb Repressive Complex 1