{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n COMMD3–BMI1 displays a critical function in coupling epigenetic regulation to stem cell self‐renewal and oncogenic transformation. Although none of the studies explicitly analyze COMMD3, the BMI1 portion of this complex is consistently shown to be essential for maintaining the proliferative capacity of normal stem cells through repression of key cell cycle inhibitors—such as p16^INK4a and p19^Arf—and by regulating chromatin states via its role in Polycomb repressive complex 1 (PRC1)."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In multiple tissues—including the hematopoietic, neural, and intestinal compartments—BMI1 ensures long‐term regenerative potential by promoting stem cell self‐renewal and preventing premature senescence. Its activity maintains proper gene silencing (for example, of Hox loci) and supports compensatory responses following injury."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Conversely, aberrant expression or activation of BMI1 is a common feature in various malignancies. Elevated BMI1 levels contribute to the emergence and maintenance of cancer stem cells, facilitate epithelial–mesenchymal transition, and promote resistance to conventional therapies in cancers such as leukemia, colorectal carcinoma, and head and neck tumors."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, BMI1 is instrumental in modulating higher-order chromatin compaction and executing epigenetic silencing beyond its canonical role in histone H2A ubiquitination. These chromatin‐based mechanisms further contribute to its role in transcriptional repression of tumor suppressor loci."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, the COMMD3–BMI1 complex—via the activities attributable to BMI1—emerges as a pivotal regulator of both normal tissue homeostasis and cancer progression. Its dual role in protecting stem cell function and, when deregulated, in driving malignant transformation, underscores its potential as a therapeutic target in regenerative medicine and oncology.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "In-kyung Park, Dalong Qian, Mark Kiel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature01587"}], "href": "https://doi.org/10.1038/nature01587"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12714971"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12714971"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Julie Lessard, Guy Sauvageau "}, {"type": "b", "children": [{"type": "t", "text": "Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature01572"}], "href": "https://doi.org/10.1038/nature01572"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12714970"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12714970"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Anna V Molofsky, Ricardo Pardal, Toshihide Iwashita, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature02060"}], "href": "https://doi.org/10.1038/nature02060"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14574365"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14574365"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Atsushi Iwama, Hideyuki Oguro, Masamitsu Negishi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Enhanced self-renewal of hematopoietic stem cells mediated by the polycomb gene product Bmi-1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Immunity (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.immuni.2004.11.004"}], "href": "https://doi.org/10.1016/j.immuni.2004.11.004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15589172"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15589172"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Eugenio Sangiorgi, Mario R Capecchi "}, {"type": "b", "children": [{"type": "t", "text": "Bmi1 is expressed in vivo in intestinal stem cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng.165"}], "href": "https://doi.org/10.1038/ng.165"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18536716"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18536716"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Hua Tian, Brian Biehs, Søren Warming, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature10408"}], "href": "https://doi.org/10.1038/nature10408"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21927002"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21927002"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Gennadi V Glinsky, Olga Berezovska, Anna B Glinskii "}, {"type": "b", "children": [{"type": "t", "text": "Microarray analysis identifies a death-from-cancer signature predicting therapy failure in patients with multiple types of cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI23412"}], "href": "https://doi.org/10.1172/JCI23412"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15931389"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15931389"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Ulrich Wellner, Jörg Schubert, Ulrike C Burk, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Cell Biol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncb1998"}], "href": "https://doi.org/10.1038/ncb1998"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19935649"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19935649"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Muh-Hwa Yang, Dennis Shin-Shian Hsu, Hsei-Wei Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Bmi1 is essential in Twist1-induced epithelial-mesenchymal transition."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Cell Biol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncb2099"}], "href": "https://doi.org/10.1038/ncb2099"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20818389"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20818389"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Antonija Kreso, Peter van Galen, Nicholas M Pedley, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Self-renewal as a therapeutic target in human colorectal cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Med (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nm.3418"}], "href": "https://doi.org/10.1038/nm.3418"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24292392"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24292392"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Ru Cao, Yu-Ichi Tsukada, Yi Zhang "}, {"type": "b", "children": [{"type": "t", "text": "Role of Bmi-1 and Ring1A in H2A ubiquitylation and Hox gene silencing."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2005.12.002"}], "href": "https://doi.org/10.1016/j.molcel.2005.12.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16359901"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16359901"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Lígia Tavares, Emilia Dimitrova, David Oxley, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RYBP-PRC1 complexes mediate H2A ubiquitylation at polycomb target sites independently of PRC2 and H3K27me3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cell.2011.12.029"}], "href": "https://doi.org/10.1016/j.cell.2011.12.029"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22325148"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22325148"}]}]}]}