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Abstract

Glioblastoma multiforme (GBM) is a devastating type of brain cancer characterized by infiltrative and aggressive growth. Transcriptional dysregulation is likely a key regulator of tumor initiation and plasticity. One transcription factor that has emerged as a potential novel regulator of these processes is myelin transcription factor 1-like (MYT1L). While it has been shown that MYT1L can drive neuronal differentiation and may play a role in suppressing GBM, it remains unclear whether MYT1L can also regulate tumor initiation and/or glioma cell plasticity. In my doctoral study, I investigated whether loss of MYT1L can induce tumor formation in post-mitotic neurons and whether MYT1L regulates GBM subtype identity. Genetic deletion of MYT1L in mature neurons of adult mice impaired the expression of neuronal genes but did not induce brain tumor formation. Unexpectedly, I found that genetic deletion of the tumor suppressors PTEN and TP53 could induce tumor formation in post-mitotic neurons. Additional deletion of MYT1L resulted in enhanced lethality and sudden death of mice. In a cerebral organoid model, I examined the effects of MYT1L on human brain tumorigenesis. In this model, loss of MYT1L in combination with mutation of canonical GBM tumor suppressors caused increased cell expansion, supporting the hypothesis that MYT1L is a brain tumor suppressor. Furthermore, MYT1L overexpression in patient-derived glioma cell lines decreased cell invasion and proliferation. Mechanistically, activator/Repressor-fusion experiments showed that MYT1L acts predominantly as a transcriptional repressor to downregulate proliferation and invasion. To further explore the molecular mechanism of MYT1L on glioma cell fate, I performed transcriptomic analysis. Interestingly, gene signature analysis revealed that MYT1L switched the identity from a mesenchymal-like GBM subtype towards a proneural/NPC-like GBM subtype, a cancer subtype with better prognosis. The correlation of MYT1L expression in the proneural subtype was also found in patient datasets. Overall, my work uncovered a novel mechanism in which MYT1L blocks cell fate plasticity to prevent dedifferentiation and tumor initiation and highlights MYT1L as a potential and repressive master regulator of NPC-like cell states in glioblastoma. These findings might lead towards subtype-specific treatments for glioma patients, which could prevent tumor progression towards more severe subtypes.