MYB-QKI Rearrangements in Angiocentric Glioma Drive Tumorigenicity Through a Tripartite Mechanism

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Bandopadhayay P, Ramkissoon LA, Jain P, Bergthold G, Wala J, Zeid R, Schumacher SE, Urbanski L, O'Rourke R, Gibson WJ, Pelton K, Ramkissoon SH, Han HJ, Zhu Y, Choudhari N, Silva A, Boucher K, Henn RE, Kang YJ, Knoff D, Paolella BR, Gladden-Young A, Varlet P, Pages M, Horowitz PM, Federation A, Malkin H, Tracy AA, Seepo S, Ducar M, Van Hummelen P, Santi M, Buccoliero AM, Scagnet M, Bowers DC, Giannini C, Puget S, Hawkins C, Tabori U, Klekner A, Bognar L, Burger PC, Eberhart C, Rodriguez FJ, Hill DA, Mueller S, Haas-Kogan DA, Phillips JJ, Santagata S, Stiles CD, Bradner JE, Jabado N, Goren A, Grill J, Ligon AH, Goumnerova L, Waanders AJ, Storm PB, Kieran MW, Ligon KL, Beroukhim R, Resnick AC
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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.