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Jessica Tsai, Paloma Cejas, Marissa Coppola, Dayle Wang, Smruti Patel, David Wu, Phonepasong Arounleut, Xin Wei, Ningxuan Zhou, Sudeepa Syamala, Frank Dubois, Kristine Pelton, Jayne Vogelzang, Cecilia Sousa, Audrey Baguette, Xiaolong Chen, Alexandra Condurat, Sarah Dixon-Clarke, Kevin Zhou, Sophie Lu, Elizabeth Gonzalez, Madison Chacon, Jeromy Digiacomo, Rushil Kumbhani, Dana Novikov, Maria Tsoli, David Ziegler, Uta Dirksen, Natalie Jager, Gnana Prakash Balsubramanian, Christof Kramm, Michaela Nathrath, Stefan Bielack, Suzanne Baker, Jinghui Zhang, James McFarland, Gad Getz, Francois Aguet, Nada Jabado, Olaf Witt, Stefan Pfister, Keith Ligon, Volker Hovestadt, Claudia Kleinman, Henry Long, David Jones, Pratiti Bandopadhayay, Timothy Phoenix, DIPG-20. DELINEATING MEDIATORS OF ONCOGENESIS IN FOXR2-EXPRESSING DIFFUSE MIDLINE GLIOMAS, Neuro-Oncology, Volume 25, Issue Supplement_1, June 2023, Page i17, https://doi.org/10.1093/neuonc/noad073.067
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Abstract
Diffuse midline gliomas (DMGs) are a universally fatal brain tumor of childhood. While histone mutations are a critical tumor initiating event, they are insufficient to drive gliomagenesis. Histone mutations co-occur with somatic alterations in other pathways including TP53, MAPK, and MYC signaling. However, the mechanisms through which these pathways are activated have not been fully elucidated.
We applied an integrative approach using transcriptomics, epigenetics, proteomics, in vitro cancer models, and in vivo mouse models to systematically evaluate how FOXR2 mediates gliomagenesis.
We have recently found that a subset of DMGs aberrantly express FOXR2, a forkhead transcription factor. FOXR2 is both sufficient to enhance tumor formation, and necessary for FOXR2-expressing DMGs. While FOXR2 indeed enhances MYC protein stability, FOXR2 exerts oncogenesis through MYC-independent functions and specifically hijacks E26-transformation specific (ETS) transcriptional circuits and FOXR2 DNA-binding is highly enriched at ETS motifs. We have performed proteomic and phospho-proteomic analysis of FOXR2-expressing human neural stem cells to identify proteins and phospho-sites that are highly enriched in FOXR2-expressing cells.
Taken together, this study elucidates how FOXR2 interacts with ETS transcription factors to mediate oncogenesis in FOXR2-expressing diffuse midline gliomas.
