RB1-EBF3 AXIS CONTRIBUTES TO THE DEVELOPMENT OF PRIMITIVE NEURONAL COMPONENT IN GLIOBLASTOMA PROMOTING STEMNESS AND INVASION AND REPRESSING DIFFERENTIATION. undefined

Glioblastoma (GBM) is the most frequent malignant central nervous system (CNS) tumour in adults, characterised by an extensive intra and inter-tumoural heterogeneity. Among the identified histological patterns, the glioblastoma with primitive neuronal component (GBM- PNC) is a rare variant described as GBM with well-demarcated nodules containing cells with primitive neuronal differentiation and anaplastic PNET-like features. This entity is frequently misdiagnosed and large clinical studies are lacking. It has been recently reported that GBM- PNCs frequently show alterations in the RB pathway, suggesting that inactivation of RB1 may be a driving mechanism for the development of GBM-PNC. In the present work we collected and characterised a remarkable cohort of this rare GBM variant and we identified Early B-Factor 3 (EBF3) as a specific biomarker selectively expressed in the PNC component. Furtherly, we investigated in vitro the biological function of EBF3 by means of a knockout versus overexpression model of Glioma stem cells. We provide evidence that the RB1-EBF3 axis contributes to the development of the PNC component promoting stemness, invasion and repressing glial differentiation. Overall, data contribute to shed light on the origin and evolution of this rare tumour entity and support the hypothesis that GBM-PNC originates from a common glial precursor by means of early common mutations, such as RB1 alterations, a recognized hallmark of GBM-PNC. These alterations, that include CDK4 and E2F upregulation, may contribute to tumour instability with the emergence of a subpopulation of undifferentiated neuroectodermal progenitors leading to the expansion of the PNC component through the RB1-MYC-EBF3 pathway activation.