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

Cancer Cell. 2018 Mar 12;33(3):435-449.e6. doi: 10.1016/j.ccell.2018.02.006.


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.

Keywords: BCL2; CRX; MAF; NRL; apoptosis; medulloblastoma; photoreceptor; retina.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic-Leucine Zipper Transcription Factors / genetics*
  • Cell Differentiation / genetics
  • Cerebellar Neoplasms / genetics
  • Eye Proteins / genetics*
  • Homeodomain Proteins / genetics*
  • Humans
  • Medulloblastoma / genetics*
  • Mice, Nude
  • Retina / pathology
  • Trans-Activators / genetics*
  • Transcription, Genetic / genetics


  • Basic-Leucine Zipper Transcription Factors
  • Eye Proteins
  • Homeodomain Proteins
  • NRL protein, human
  • Nrl protein, mouse
  • Trans-Activators
  • cone rod homeobox protein