Journal
NATURE
Volume 609, Issue 7929, Pages 1021-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41586-022-05215-w
Keywords
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Categories
Funding
- NIH [R01NS106155, R01CA159859, R01CA255369, R01-NS080390, R01-NS095733, R37 NS095733, R21 NS117848]
- Pediatric Brain Tumor Foundation
- Terry Fox Research Institute
- Canadian Institutes of Health Research
- Cure Search Foundation
- Matthew Larson Foundation (IronMatt)
- b.r.a.i.n.child
- Meagan's Walk
- SWIFTY Foundation
- Brain Tumor Charity
- Genome Canada
- Genome BC
- Genome Quebec
- Ontario Research Fund
- Worldwide Cancer Research
- V-Foundation for Cancer Research
- Government of Ontario
- Canadian Cancer Society Research Institute Impact grant
- Cancer Research UK Brain Tumor Award
- Stand Up To Cancer (SU2C) St Baldrick's Pediatric Dream Team Translational Research Grant [SU2C-AACR-DT1113]
- SU2C Canada Cancer Stem Cell Dream Team Research Funding [SU2C-AACR-DT-19-15]
- Garron Family Chair in Childhood Cancer Research at the Hospital for Sick Children
- University of Toronto
- Canadian Institutes of Health Research (CIHR)
- CancerCare Manitoba Foundation
- Japan Society for the Promotion of Science (JSPS) KAKENHI [21K21001]
- National Cancer Center Research and Development Funds [2021-A-1]
- CIHR [PJT-156086]
- Fonds de Recherche du Quebec-Sante (FRQS)
- NSERC [RGPIN-2016-04911]
- Brain and Behavior Young Investigator Award
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Medulloblastoma (MB) is a pediatric embryonal neoplasm of the hindbrain with subtypes including Sonic hedgehog MB, WNT MB and G4 MB. Somatic mutations in G4 MB converge on the core binding factor alpha (CBFA) complex, and knocking down OTX2 can relieve differentiation blockage.
Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong linksto early development of the hindbrain(1-4). Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage(5-8). By contrast, mutationsthat activate WNT signalling lead to WNT MB in the lower RL9,10. However, little is known about the more commonly occurringgroup 4 (G4) MB, which isthought to arise in the unipolar brush cell lineage(3,4). Here we demonstrate that somatic mutationsthat 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 ofthe cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2in model systems relieves this differentiation blockade, which allows MB cellsto spontaneously proceed along normal developmental differentiation trajectories. The specific nature ofthe split human RL, which is destined togenerate most ofthe neurons in the human brain, and its high level of susceptible EOMES(+)K167(+) unipolar brush cell progenitor cells probably predisposes our speciesto the development of G4 MB.
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