NRL and CRX Define Photoreceptor Identity and Reveal Subgroup-Specific Dependencies in Medulloblastoma

Cancer cells often express differentiation programs unrelated to their tissue of origin, although the contribution of these aberrant phenotypes to malignancy is poorly understood. An aggressive subgroup of medulloblastoma, a malignant pediatric brain tumor of the cerebellum, expresses a photoreceptor differentiation program normally expressed in the retina. We establish that two photoreceptor-specific transcription factors, NRL and CRX, are master regulators of this program and are required for tumor maintenance in this subgroup. Beyond photoreceptor lineage genes, we identify BCL-XL as a key transcriptional target of NRL and provide evidence substantiating anti-BCL therapy as a rational treatment opportunity for select MB patients. Our results highlight the utility of studying aberrant differentiation programs in cancer and their potential as selective therapeutic vulnerabilities. [Display omitted] •NRL and CRX are master regulators of the group 3 MB photoreceptor program•Photoreceptor transcriptional program is a dependency in group 3 MB•NRL protects MB from apoptosis by inducing BCL-XL expression•BCL-XL as a potential therapeutic target in group 3 MB Garancher et al. show that NRL and CRX are master transcriptional regulators of a photoreceptor-specific differentiation program critical for group 3 medulloblastoma (MB) maintenance. They identify BCL-XL as a key NRL target and provide evidence supporting anti-BCL therapy as a strategy for some MB patients.