Failure of human rhombic lip differentiation underlies medulloblastoma formation

Nature. 2022 Sep;609(7929):1021-1028. doi: 10.1038/s41586-022-05215-w. Epub 2022 Sep 21.


Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain1-4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage5-8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES+KI67+ unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.

Publication types

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

MeSH terms

  • Cell Differentiation* / genetics
  • Cell Lineage
  • Cerebellar Neoplasms* / classification
  • Cerebellar Neoplasms* / genetics
  • Cerebellar Neoplasms* / pathology
  • Cerebellum / embryology
  • Cerebellum / pathology
  • Core Binding Factor alpha Subunits / genetics
  • Hedgehog Proteins / metabolism
  • Histone Demethylases
  • Humans
  • Ki-67 Antigen / metabolism
  • Medulloblastoma* / classification
  • Medulloblastoma* / genetics
  • Medulloblastoma* / pathology
  • Metencephalon* / embryology
  • Metencephalon* / pathology
  • Muscle Proteins
  • Mutation
  • Otx Transcription Factors / deficiency
  • Otx Transcription Factors / genetics
  • Repressor Proteins
  • T-Box Domain Proteins / metabolism
  • Transcription Factors


  • CBFA2T2 myeloid-transforming gene-related protein
  • CBFA2T3 protein, human
  • Core Binding Factor alpha Subunits
  • EOMES protein, human
  • Hedgehog Proteins
  • Ki-67 Antigen
  • Muscle Proteins
  • OTX2 protein, human
  • Otx Transcription Factors
  • PRDM6 protein, human
  • Repressor Proteins
  • T-Box Domain Proteins
  • Transcription Factors
  • core binding factor alpha
  • Histone Demethylases
  • KDM6A protein, human