MB-09AGGRESSIVE MEDULLOBLASTOMA SUBVERTS THE PHOTORECEPTOR SPECIFIC TRANSCRIPTION FACTOR NRL

Medulloblastoma (MB) is the most common malignant brain tumor of childhood arising in the cerebellum. Although multimodal treatments have significantly increased the survival, 20% to 30% of patients remain incurable. Transcriptomic studies identified four MB subgroups. Among those, the group 3 is of poorer prognosis, frequently metastatic and refractory to current therapies. It is characterized by a photoreceptor differentiation program composed of genes expressed in the retina in physiological conditions. Cancer cells often express such aberrant differentiation programs unrelated to their tissue of origin. They result, in some instances, from cancer cell plasticity but are not thought to contribute to cancer progression. Our work established that the retina-specific photoreceptor differentiation program is instrumental to MB progression. Using transcriptomic data from patient samples and different models including patient-derived xenografts, we showed that group 3 MBs subvert NRL, a major transcription factor of this program, to its profit and thus, identified one key driver event of this poorly characterized MB subgroup. We further demonstrated that NRL protects MB from apoptosis by controlling the expression of the anti-apoptotic BCL-XL gene. Accordingly, we also showed that anti-BCL therapies could represent an alternative therapeutic strategy for this pediatric tumor.