Developmental stage and cellular context determine oncogenic and molecular outcomes of Ezh2Y641F mutation in hematopoiesis
Year: 2026
Type: article
Abstract: Mutations in the histone methyltransferase enhancer of zeste homolog 2 (EZH2), particularly the neomorphic Y641F hot spot mutation, are implicated in hematologic malignancies. However, how developmental timing and cellular context influence their oncogenic potential remains poorly understood. Here, we used a conditional Ezh2Y641F allele with multiple tissue-specific Cre drivers to investigate the effects of these mutations across hematopoietic development. We found that ubiquitous or early expression of Ezh2Y641F led to bone marrow failure and reduced survival with no evidence of transformation. In contrast, expression in committed B cells using CD19-Cre consistently induced B-cell lymphomas, underscoring a context- and stage-specific requirement for transformation. Transcriptomic analysis of B-cell progenitors revealed distinct gene expression changes between Cre models, including interferon signaling and upregulation of guanylate-binding proteins (GBPs) in Mx1-Cre Ezh2Y641F mutants. We identified a redistribution of histone 3 lysine 27 trimethylation at the GBP locus and showed that GBP2 overexpression impairs multilineage hematopoiesis by promoting apoptosis and skewing differentiation. These findings demonstrate that the oncogenic potential of Ezh2Y641F is highly dependent on the cellular environment in which it is expressed and that the timing of mutation acquisition critically shapes the impact of EZH2 on hematopoiesis and disease outcome.
Source: UNC Libraries
DOI: 10.17615/n0ar-8m25
Institution: University of North Carolina at Chapel Hill
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Ministerio de Ciencia, Tecnología e Innovación, Welch Foundation, American Heart Association, Cancer Research Foundation, Alexander von Humboldt-Stiftung, Leukemia Research Foundation, University of Nevada, Las Vegas, University of Virginia, Wellcome Trust, Solar Technologies go Hybrid, Ontario Research Foundation, Comunidad de Madrid, UK Research and Innovation, Ministerio de Ciencia, Innovación y Universidades, Chan Zuckerberg Initiative, Faraday Institution, Korea Toray Science Foundation, Royal Society, European Commission, European Cooperation in Science and Technology, National Research Foundation, Deutsche Forschungsgemeinschaft, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Rijksuniversiteit Groningen, Canada Research Chairs, Fundação de Amparo à Pesquisa do Estado de São Paulo, National Natural Science Foundation of China, Academia Sinica, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Seoul National University, Research Grants Council, University Grants Committee, Else Kröner-Fresenius-Stiftung, Eusko Jaurlaritza, Euskal Herriko Unibertsitatea, Conselho Nacional de Desenvolvimento Científico e Tecnológico, National Research Foundation of Korea, Israel Science Foundation, Max-Planck-Gesellschaft, Princess Nourah Bint Abdulrahman University, Vetenskapsrådet, China Scholarship Council, Chinese University of Hong Kong, Universitätsklinikum Regensburg, Medizinische Universität Wien, Changhai Hospital of Shanghai, Novo Nordisk Fonden, Innovation and Technology Fund, Junta de Comunidades de Castilla-La Mancha, Science and Technology Innovation as a Whole Plan Projects of Shaanxi Province, Thailand Science Research and Innovation, Advanced Materials and Bioengineering Research, Board of the Swiss Federal Institutes of Technology, Gauss Centre for Supercomputing, National Institutes of Health, Centers for Disease Control and Prevention, U.S. Public Health Service, Horizon 2020 Framework Programme, Natural Sciences and Engineering Research Council of Canada, Engineering and Physical Sciences Research Council, Japan Society for the Promotion of Science, Instituto de Salud Carlos III, Balliol College, University of Oxford, Rijksinstituut voor Volksgezondheid en Milieu, European Regional Development Fund, Agencia Estatal de Investigación, National Key Research and Development Program of China, Zernike Institute for Advanced Materials, Rijksuniversiteit Groningen, Basic and Applied Basic Research Foundation of Guangdong Province, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of General Medical Sciences, Center for Information Technology, Division of Chemical, Bioengineering, Environmental, and Transport Systems, Division of Undergraduate Education, National Renewable Energy Laboratory, H2020 European Research Council, H2020 Research Infrastructures, HORIZON EUROPE Digital, Industry and Space, HORIZON EUROPE European Research Council, Exacte en Natuurwetenschappen, Wellcome Leap, NextGenerationEU, NCCR Catalysis
OpenAlex ID: W7163561211