Abstract 4372: MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism

Abstract

Abstract Diffuse pediatric low-grade gliomas (PLGGs) are among the most common solid tumors in children. While BRAF mutations and MYBL1 rearrangements have recently been identified as diagnostic and treatment related oncogenic drivers in pediatric gangliogliomas and diffuse astrocytomas, respectively, for the majority of diffuse PLGGs the oncogenic driver(s) remain unknown. Recent efforts to identify new oncogenic drivers lack sufficient power to determine the true frequency of alterations in genes or to associate specific alterations with rare histological subtypes, such as Angiocentric gliomas (AGs). To address this issue, we performed genomic analysis of new and published data from 249 PLGGs including 19 AGs. We identified MYB-QKI fusions as a specific, recurrent, single candidate driver event in AGs. Although MYB is expressed during early brain development in a subset of progenitor cells, it is not known to play a role in normal cortical brain where AGs frequently occur. In vitro functional studies show MYB-QKI rearrangements promote tumorigenesis in mouse neural stem cells (mNSCs) through three mechanisms: MYB activation by truncation, enhancer translocation driving aberrant MYB-QKI expression, and hemizygous loss of the tumor suppressor QKI. Expression of the MYB-QKI fusion increases mNSC proliferation and activates known MYB target genes including KIT and CDK6. H3K27ac enhancer profiling of AG tumors demonstrate active enhancer elements are translocated proximally to the MYB promoter while in vitro promoter assays confirmed that QKI enhancer sequences activate the MYB promoter. Together with functional studies demonstrating that MYB-QKI can also bind and activate the MYB promoter, these data support a positive auto-regulatory feed-back loop model in which active MYB-QKI is able to drive its own expression through enhanced MYB-promoter-activation. Furthermore, when injected orthotopically into immunodeficient mice, expression of truncated MYB or MYB-QKI is sufficient to induce tumor formation that recapitulate histologic and immunophenotypic characteristics of AGs. Analysis of AG specific MYB-QKI fusion represents the first example of how a single driver rearrangement simultaneously transforms cells via three genetic and epigenetic mechanisms in a cancer. Citation Format: Lori Ramkissoon, Pratiti Bandopadhayay, Payal Jain, Guillaume Bergthold, Adam Resnick, Rameen Beroukhim, Keith Ligon. MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4372.