Globally altered epigenetic landscape and delayed osteogenic differentiation in H3.3-G34W-mutant giant cell tumor of bone

Pavlo Lutsik, Annika Baude, Daniela Mancarella, Simin Öz, Alexander Kühn, Reka Toth, Joschka Hey, Umut H. Toprak, Jinyeong Lim, Viet Ha Nguyen, Chao Jiang, Anand Mayakonda, Mark Hartmann, Felix Rosemann, Kersten Breuer, Dominik Vonficht, Florian Grünschläger, Suman Lee, Maren Kirstin Schuhmacher, Denis Kusevic, Anna Jauch, Dieter Weichenhan, Jozef Zustin, Matthias Schlesner, Simon Haas, Joo Hyun Park, Yoon Jung Park, Udo Oppermann, Albert Jeltsch, Florian Haller, Jörg Fellenberg, Anders M. Lindroth () and Christoph Plass ()
Additional contact information
Pavlo Lutsik: German Cancer Research Center (DKFZ)
Annika Baude: German Cancer Research Center (DKFZ)
Daniela Mancarella: German Cancer Research Center (DKFZ)
Simin Öz: German Cancer Research Center (DKFZ)
Alexander Kühn: German Cancer Research Center (DKFZ)
Reka Toth: German Cancer Research Center (DKFZ)
Joschka Hey: German Cancer Research Center (DKFZ)
Umut H. Toprak: German Cancer Research Center (DKFZ)
Jinyeong Lim: National Cancer Center
Viet Ha Nguyen: National Cancer Center
Chao Jiang: University of Oxford
Anand Mayakonda: German Cancer Research Center (DKFZ)
Mark Hartmann: Division of Translational Medical Oncology, National Center for Tumor Diseases (NCT) & German Cancer Research Center (DKFZ)
Felix Rosemann: German Cancer Research Center (DKFZ)
Kersten Breuer: German Cancer Research Center (DKFZ)
Dominik Vonficht: Ruprecht Karl University of Heidelberg
Florian Grünschläger: Ruprecht Karl University of Heidelberg
Suman Lee: National Cancer Center
Maren Kirstin Schuhmacher: University of Stuttgart
Denis Kusevic: University of Stuttgart
Anna Jauch: Ruprecht Karl University of Heidelberg
Dieter Weichenhan: German Cancer Research Center (DKFZ)
Jozef Zustin: University Medical Center Hamburg-Eppendorf
Matthias Schlesner: German Cancer Research Center (DKFZ)
Simon Haas: German Cancer Research Center (DKFZ)
Joo Hyun Park: Department of Nutritional Science and Food Management, Ewha Womans University
Yoon Jung Park: Department of Nutritional Science and Food Management, Ewha Womans University
Udo Oppermann: University of Oxford
Albert Jeltsch: University of Stuttgart
Florian Haller: University Hospital Erlangen, Friedrich Alexander University Erlangen-Nürnberg
Jörg Fellenberg: Orthopaedic University Hospital Heidelberg, Ruprecht Karl University of Heidelberg
Anders M. Lindroth: National Cancer Center
Christoph Plass: German Cancer Research Center (DKFZ)

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract The neoplastic stromal cells of giant cell tumor of bone (GCTB) carry a mutation in H3F3A, leading to a mutant histone variant, H3.3-G34W, as a sole recurrent genetic alteration. We show that in patient-derived stromal cells H3.3-G34W is incorporated into the chromatin and associates with massive epigenetic alterations on the DNA methylation, chromatin accessibility and histone modification level, that can be partially recapitulated in an orthogonal cell line system by the introduction of H3.3-G34W. These epigenetic alterations affect mainly heterochromatic and bivalent regions and provide possible explanations for the genomic instability, as well as the osteolytic phenotype of GCTB. The mutation occurs in differentiating mesenchymal stem cells and associates with an impaired osteogenic differentiation. We propose that the observed epigenetic alterations reflect distinct differentiation stages of H3.3 WT and H3.3 MUT stromal cells and add to H3.3-G34W-associated changes.

Date: 2020
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DOI: 10.1038/s41467-020-18955-y

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