39 TRANSCRIPTION FACTOR MEDIATED RESCUE OF GLIOBLASTOMA DIFFERENTIATION FAILURE

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Abstract Glioblastomas (GBMs) contain undifferentiated and more differentiated malignant cells, mixed with nonmalignant microenvironmental cells. Undifferentiated cells consist of quiescent stem-like and proliferative progenitor-like populations that drive tumour growth and contribute to treatment resistance. Driver precursors can be isolated from GBM as GBM stem cells (GSCs), which retain some similarities to normal neural stem cells (NSCs). Our group previously discovered that a key transcription factor of NSCs, achaete-scute family bHLH transcription factor 1 (ASCL1), is required and sufficient to drive GSCs towards a neuronal fate and attenuate tumourigenicity. Despite their similarities, a major difference between GSCs and NSCs is the ability to undergo terminal fate commitment. In this study, we studied how to overcome differentiation failure in response to activation of transcription factors, with a focus on ASCL1-mediated neuronal differentiation in the context of cancer (GSCs) and normal development (NSCs). In cancer, we found that GSCs are unable to reach the state of mature neuronal differentiation seen in NSCs. Malignant differentiation instead displays lineage infidelity and a persistent neural progenitor program, contributing to lineage plasticity and terminal differentiation failure. Through sequencing methods, we show that the myelin transcription factor (MYT) gene family is misregulated in malignant differentiation. Restoration of MYT1 expression specifically rescues neuronal terminal differentiation in GSCs. These data demonstrate a novel approach to achieve terminal neuronal differentiation in GBM. We propose that driving terminal differentiation of GBM cells through transcription factor manipulation may overcome the cellular and genetic heterogeneity of GBM, and restrict the growth of malignant populations.

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