Venue: Edificio Povo 2, via Sommarive nr. 9, Povo (Tn) - Room B101
At 2:00 p.m.
- Luca Tiberi - Pierre Vanderhaeghen lab, ULB, Brussels, Belgium.
Disrupted differentiation during development can lead to oncogenesis, but the underlying mechanisms remain poorly understood. One striking example of the tight link between brain development and oncogenesis is medulloblastoma (MB), the most prevalent malignant brain tumor in children. MB is thought to be caused in part by deregulation of SHH pathways in stem cells during brain development. The SHH medulloblastoma subtype accounts for approximately 25% of MB and is mainly caused by aberrant activation of the SHH pathway in granule neuron precursors (GNPs). This cellular population was found to constitute the main cells of origin of SHH medulloblastoma in the mouse. We identified BCL6, a transcriptional repressor as a pivotal factor required for neurogenesis and tumor suppression of SHH MB:
- BCL6 is required for neurogenesis of cerebellar granule neurons.
- BCL6 is both necessary and sufficient to prevent the development of GNPs-derived MB in the mouse and can block the growth of human MB cells in vitro.
- BCL6 neurogenic and oncosuppressor effects rely on direct transcriptional repression of Gli1/2 effectors of the SHH pathway, through recruitment of BCOR co-repressor and SIRT1 deacetylase.
Our findings identify the BCL6/BCOR/SIRT1 complex as a potent repressor of the SHH pathway in normal and transformed stem cells, with direct diagnostic and/or therapeutic relevance for SHH medulloblastoma.