Lgg-06. Functional and Therapeutic Relevance of Myb-qki-induced Transcriptional Events to Gliomagenesis
Year: 2017
Type: conference-abstract
Abstract: INTRODUCTION: The large-scale genomic analysis of pediatric low-grade gliomas recently conducted in our laboratories identified the MYB-QKI fusion as a genetic driver of angiocentric glioma. MYB-QKI retains the MYB HTH DNA-binding domain and functions as a transcription factor. These findings present the opportunity to design the first targeted therapy for this tumor. METHODS: We investigated the functional significance of MYB-QKI-driven transcriptional events using the Connectivity Map, a catalog of transcriptional signatures from disease states and genetic and pharmacological perturbation experiments. To identify potential dependencies in the MYB-QKI phenotype, we focused on genetic perturbagens, such as knockdown or overexpression of single genes, with transcriptional signatures similar to that of MYB-QKI. To identify drugs with potential activity against MYB-QKI-driven glioma, we focused on pharmacological perturbagens with transcriptional signatures that oppose that of MYB-QKI. Findings were validated empirically in functional assays. RESULTS: Expression analysis identified CDK6 and the tyrosine kinase receptor c-KIT as two of the genes most highly upregulated by MYB-QKI compared to control. Connectivity Map analysis showed that overexpression of CDK6 as a single gene produced a transcription signature highly similar to that of MYB-QKI, suggesting that CDK6 may be a key mediator of the MYB-QKI phenotype. The Connectivity Map also suggested that pharmacological inhibition of signaling pathways downstream of tyrosine kinase receptors produced an opposing signature to that of MYB-QKI. Since expression of the tyrosine kinase receptor c-KIT is highly induced by MYB-QKI, this result suggested that c-KIT inhibition may be therapeutically effective in MYB-QKI-driven glioma. Functional assays confirmed that the c-KIT inhibitor dasatinib could inhibit the growth of MYB-QKI-expressing neural stem cells but not that of control cells. CONCLUSIONS: Exploration of the MYB-QKI transcriptional signature with the Connectivity Map suggests that CDK6 and c-KIT inhibition warrant further investigation as potential therapies for MYB-QKI tumors. *Co-First Authors: Dr. Cecile Rouleau and Dr. Pratiti Bandopadayay. Co-Last Authors: Dr. Keith Ligon and Dr. Rameen Beroukhim
Source: Neuro-Oncology
Institution: Dana-Farber Cancer Institute
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2617277148