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MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism

2016; Nature Portfolio; Volume: 48; Issue: 3 Linguagem: Inglês

10.1038/ng.3500

1546-1718

Pratiti Bandopadhayay, Lori Ramkissoon, Payal Jain, Guillaume Bergthold, Jeremiah A. Wala, Rhamy Zeid, Steven E. Schumacher, Laura M. Urbanski, Ryan O’Rourke, William J. Gibson, Kristine Pelton, Shakti Ramkissoon, Harry Han, Yuankun Zhu, Namrata Choudhari, Amanda Silva, Katie Boucher, Rosemary E. Henn, Yun Jee Kang, David Knoff, Brenton R. Paolella, Adrianne Gladden-Young, Pascale Varlet, Mélanie Pagès, Peleg Horowitz, Alexander Federation, Hayley Malkin, Adam Tracy, Sara Seepo, Matthew D. Ducar, Paul Van Hummelen, Mariarita Santi, Anna Maria Buccoliero, Mirko Scagnet, Daniel C. Bowers, Caterina Giannini, Stéphanie Puget, Cynthia Hawkins, Uri Tabori, Álmos Klekner, László Bognár, Peter C. Burger, Charles G. Eberhart, Fausto J. Rodríguez, D. Ashley Hill, Sabine Mueller, Daphne A. Haas‐Kogan, Joanna J. Phillips, Sandro Santagata, Charles D. Stiles, James E. Bradner, Nada Jabado, Alon Goren, Jacques Grill, Azra H. Ligon, Liliana Goumnerova, Angela J. Waanders, Phillip B. Storm, Mark W. Kieran, Keith L. Ligon, Rameen Beroukhim, Adam Resnick,

Protein Degradation and Inhibitors

Keith Ligon, Adam Resnick, Rameen Beroukhim and colleagues identify MYB-QKI fusions in angiocentric gliomas and show that these rearrangements promote tumorigenesis through activation of MYB by truncation, enhancer translocation driving aberrant MYB-QKI expression and hemizygous loss of QKI. Angiocentric gliomas are pediatric low-grade gliomas (PLGGs) without known recurrent genetic drivers. We performed genomic analysis of new and published data from 249 PLGGs, including 19 angiocentric gliomas. We identified MYB-QKI fusions as a specific and single candidate driver event in angiocentric gliomas. In vitro and in vivo functional studies show that MYB-QKI rearrangements promote tumorigenesis through three mechanisms: MYB activation by truncation, enhancer translocation driving aberrant MYB-QKI expression and hemizygous loss of the tumor suppressor QKI. To our knowledge, this represents the first example of a single driver rearrangement simultaneously transforming cells via three genetic and epigenetic mechanisms in a tumor.