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Knock-down of oncohistone H3F3A-G34W counteracts the neoplastic phenotype of giant cell tumor of bone derived stromal cells

Giant cell tumors of bone (GCTB) are semi-malignant tumors associated with extensive osteolytic defects and massive bone destructions. They display a locally aggressive behavior and a very high recurrence rate. Recently, a single mutation has been identified in GCTB affecting the H3F3A gene coding f...

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Main Authors: Fellenberg, Jörg (Author) , Sähr, Heiner (Author) , Mancarella, D. (Author) , Plass, C. (Author) , Lindroth, A. M. (Author) , Westhauser, Fabian (Author) , Lehner, Burkhard (Author) , Ewerbeck, Volker (Author)
Format: Article (Journal)
Language:English
Published: 8 February 2019
In: Cancer letters
Year: 2019, Volume: 448, Pages: 61-69
ISSN:1872-7980
DOI:10.1016/j.canlet.2019.02.001
Online Access:Verlag, Volltext: https://doi.org/10.1016/j.canlet.2019.02.001
Verlag, Volltext: http://www.sciencedirect.com/science/article/pii/S0304383519300631
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Author Notes:J. Fellenberg, H. Sähr, D. Mancarella, C. Plass, A.M. Lindroth, F. Westhauser, B. Lehner, V. Ewerbeck
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Summary:Giant cell tumors of bone (GCTB) are semi-malignant tumors associated with extensive osteolytic defects and massive bone destructions. They display a locally aggressive behavior and a very high recurrence rate. Recently, a single mutation has been identified in GCTB affecting the H3F3A gene coding for the histone variant H3.3 (H3.3-G34W). The aim of this study was to investigate whether H3.3-G34W is sufficient to drive tumorigenesis in GCTB. Initially, we confirmed the high frequency of this mutation in 94% of 84 analyzed tissue samples. Using a siRNA based approach we could selectively knockdown H3.3-G34W in primary neoplastic stromal cells isolated from tumor tissue (GCTSC). H3.3-G34W knockdown caused a significant inhibition of cell proliferation, migration and colony formation capacity in vitro. Xenotransplantation of GCTSCs onto the chorioallantoic membrane of fertilized chicken eggs further demonstrated a significant impact of H3.3-G34W knockdown on tumor engraftment and growth in vivo. Our data indicate that H3.3-G34W is sufficient to drive tumorigenesis in GCTB. Apart from the application of H3.3-G34W screening as diagnostic tool, our data suggest that H3.3-G4W represents a promising target for the development of new GCTB therapies.
Item Description:Gesehen am 09.07.2019
Physical Description:Online Resource
ISSN:1872-7980
DOI:10.1016/j.canlet.2019.02.001

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