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Failure of human rhombic lip differentiation underlies medulloblastoma formation
Autoři | |
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Rok publikování | 2022 |
Druh | Článek v odborném periodiku |
Časopis / Zdroj | Nature |
Fakulta / Pracoviště MU | |
Citace | |
www | https://www.nature.com/articles/s41586-022-05215-w |
Doi | http://dx.doi.org/10.1038/s41586-022-05215-w |
Klíčová slova | human rhombic lip; failure; medulloblastoma formation |
Popis | 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. |