MYB–QKI rearrangement promotes angiocentric glioma via three genetic and epigenetic mechanisms.

  • Major finding:MYB–QKI rearrangement promotes angiocentric glioma via three genetic and epigenetic mechanisms.

  • Mechanism:MYB–QKI promotes glioma tumorigenesis via MYB truncation, enhancer translocation, and QKI loss.

  • Impact:MYB–QKI rearrangements are unique to angiocentric glioma and may serve as diagnostic markers.

Pediatric low-grade gliomas (PLGG) are a heterogeneous group of tumors, including angiocentric glioma, that often harbor MYB alterations. However, the specific alterations and their functions have not been determined in angiocentric glioma. In order to identify recurrent alterations, Bandopadhayay and colleagues analyzed whole-genome and RNA-sequencing data from 172 PLGGs, including seven angiocentric gliomas. All seven angiocentric gliomas harbored MYB translocations, including 6 MYB–QKI fusions and 1 MYB–ESR1 fusion. The MYB–QKI fusion was specific to angiocentric gliomas, and not detected in any of the tested nonangiocentric gliomas. The translocation resulted in an in-frame fusion of the MYB DNA-binding domain to the C-terminus of QKI, which encodes the RNA-binding protein Quaking. Gene expression analysis in mouse neural stem cells (mNSC) stably expressing MYBQKI indicated that MYB pathway genes were activated by MYBQKI. Furthermore, chromatin immunoprecipitation sequencing revealed that MYB–QKI predominantly bound to the MYB binding motif in enhancer regions marked by acetylation of histone H3 at lysine 27, and MYB–QKI functioned as a transcription factor that activated the MYB promoter more strongly than MYB. In normal cortical brain, the 3′ end of QKI is associated with active enhancers while the MYB locus is not, but the MYB–QKI rearrangement brought the QKI enhancers in proximity to the MYB promoter, enhancing aberrant expression of activated truncated MYB. The MYBQKI fusion was oncogenic, as its stable expression in mNSCs promoted proliferation and tumor formation in vivo. In addition, wild-type QKI is a tumor suppressor, and suppressing the first 4 exons of QKI, as occurs with the MYB–QKI translocation, increased proliferation. Together, these findings suggest that MYB-QKI is a specific oncogenic driver in angiocentric gliomas and promotes tumor growth through the oncogenic function of the MYBQKI fusion transcription factor, activation of the MYB promoter via translocation of the QKI enhancer, and loss of QKI tumor suppressor function.

Bandopadhayay P, Ramkissoon LA, Jain P, Bergthold G, Wala J, Zeid R, et al. MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism. Nat Genet 2016 Feb 1 [Epub ahead of print].

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