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Chromatin modification abnormalities by CHD7 and KMT2C loss promote medulloblastoma progression

Medulloblastoma (MB), a common malignant pediatric brain tumor arising in the cerebellum, is characterized by mutations in chromatin modifiers, highlighting the significance of chromatin modification abnormalities in its progression. While animal models have effectively demonstrated this, a comprehe...

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Main Authors: Wang, Wanchen (Author) , Kumegawa, Kohei (Author) , Chapman, Owen S. (Author) , Shiraishi, Ryo (Author) , Xiao, Zhize (Author) , Okonechnikov, Konstantin (Author) , Sun, Yang (Author) , Pfister, Stefan (Author) , Feng, Weijun (Author) , Uesaka, Naofumi (Author) , Hoshino, Mikio (Author) , Takahashi, Satoru (Author) , Korshunov, Andrey (Author) , Chavez, Lukas (Author) , Maruyama, Reo (Author) , Kawauchi, Daisuke (Author)
Format: Article (Journal)
Language:English
Published: 27 May 2025
In: Cell reports
Year: 2025, Volume: 44, Issue: 5, Pages: 1-25
ISSN:2211-1247
DOI:10.1016/j.celrep.2025.115673
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.celrep.2025.115673
Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S2211124725004449
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Author Notes:Wanchen Wang, Kohei Kumegawa, Owen S. Chapman, Ryo Shiraishi, Zhize Xiao, Konstantin Okonechnikov, Yang Sun, Stefan M. Pfister, Weijun Feng, Naofumi Uesaka, Mikio Hoshino, Satoru Takahashi, Andrey Korshunov, Lukas Chavez, Reo Maruyama, and Daisuke Kawauchi
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Summary:Medulloblastoma (MB), a common malignant pediatric brain tumor arising in the cerebellum, is characterized by mutations in chromatin modifiers, highlighting the significance of chromatin modification abnormalities in its progression. While animal models have effectively demonstrated this, a comprehensive evaluation of the oncogenic potential of these mutations remains incomplete. In this study, we use CRISPR-mediated gene editing to knock out chromatin modifier genes mutated in human SHH MB, along with the Ptch1 gene, in cerebellar granule neuron progenitors of neonatal mice. This reveals that depletion of Chd7 and Kmt2c accelerates tumor growth. Multi-layered omics analysis uncovers that inhibition of the neuronal differentiation program by chromatin dysregulation is a key signaling pathway in tumor progression. Additionally, forced expression of Neurod1, a common target of these chromatin modifiers, inhibits proliferation and promotes differentiation. These findings highlight converging chromatin modification abnormalities from distinct mutations in Sonic Hedgehog MB and suggest that epigenetic drugs activating neuronal genes have significant potential as novel treatments.
Item Description:Online verfügbar: 19. Mai 2025, Artikelversion: 27. Mai 2025
Gesehen am 18.09.2025
Physical Description:Online Resource
ISSN:2211-1247
DOI:10.1016/j.celrep.2025.115673

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