title: Maintenance of leukemic cell identity by the activity of the Polycomb complex PRC1 in mice.
abstract: Leukemia is a complex heterogeneous disease often driven by the expression of oncogenic fusion proteins with different molecular and biochemical properties. Whereas several fusion proteins induce leukemogenesis by activatingHoxgene expression (Hox-activating fusions), others impinge on different pathways that do not involve the activation ofHoxgenes (non-Hox-activating fusions). It has been postulated that one of the main oncogenic properties of the HOXA9 transcription factor is its ability to control the expression of thep16/p19tumor suppressor locus (Cdkn2a), thereby compensating Polycomb-mediated repression, which is dispensable for leukemias induced by Hox-activating fusions. We show, by genetically depleting the H2A ubiquitin ligase subunits of the Polycomb repressive complex 1 (PRC1), Ring1a and Ring1b, thatHoxa9activation cannot repressCdkn2aexpression in the absence of PRC1 and its dependent deposition of H2AK119 monoubiquitination (H2AK119Ub). This demonstrates the essential role of PRC1 activity in supporting the oncogenic potential of Hox-activating fusion proteins. By combining genetic tools with genome-wide location and transcription analyses, we further show that PRC1 activity is required for the leukemogenic potential of both Hox-activating and non-Hox-activating fusions, thus preventing the differentiation of leukemic cells independently of the expression of theCdkn2alocus. Overall, our results genetically demonstrate that PRC1 activity and the deposition of H2AK119Ub are critical factors that maintain the undifferentiated identity of cancer cells, positively sustaining the progression of different types of leukemia.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Rossi
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Karin J
authors.initials: KJ
authors.lastname: Ferrari
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Andrea
authors.identifier: 0000-0002-3344-8755
authors.initials: A
authors.lastname: Piunti
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: SriGanesh
authors.initials: S
authors.lastname: Jammula
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Fulvio
authors.initials: F
authors.lastname: Chiacchiera
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Mazzarella
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Scelfo
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.; Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, Italy.
authors.forename: Pier Giuseppe
authors.initials: PG
authors.lastname: Pelicci
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Diego
authors.identifier: 0000-0002-9879-6486
authors.initials: D
authors.lastname: Pasini
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015973:Gene Expression Regulation, Leukemic; D007938:Leukemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D009363:Neoplasm Proteins; D063150:Polycomb Repressive Complex 1
keywords: MLL-AF9; PRC1; Polycomb; histone modifications; leukemia