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Failure of human rhombic lip differentiation underlies medulloblastoma formation.

Publication ,  Journal Article
Hendrikse, LD; Haldipur, P; Saulnier, O; Millman, J; Sjoboen, AH; Erickson, AW; Ong, W; Gordon, V; Coudière-Morrison, L; Mercier, AL; Ly, M ...
Published in: Nature
September 2022
Published version (DOI) Link to item

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.

Duke Scholars

Roger Edwin McLendon
Author Roger Edwin McLendon Pathology

Published In

Nature

DOI

10.1038/s41586-022-05215-w

EISSN

1476-4687

Publication Date

September 2022

Volume

609

Issue

7929

Start / End Page

1021 / 1028

Location

England

Related Subject Headings

  • Transcription Factors
  • T-Box Domain Proteins
  • Repressor Proteins
  • Otx Transcription Factors
  • Mutation
  • Muscle Proteins
  • Metencephalon
  • Medulloblastoma
  • Ki-67 Antigen
  • Humans
 

Citation

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ICMJE
MLA
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Hendrikse, L. D., Haldipur, P., Saulnier, O., Millman, J., Sjoboen, A. H., Erickson, A. W., … Taylor, M. D. (2022). Failure of human rhombic lip differentiation underlies medulloblastoma formation. Nature, 609(7929), 1021–1028. https://doi.org/10.1038/s41586-022-05215-w
Hendrikse, Liam D., Parthiv Haldipur, Olivier Saulnier, Jake Millman, Alexandria H. Sjoboen, Anders W. Erickson, Winnie Ong, et al. “Failure of human rhombic lip differentiation underlies medulloblastoma formation.” Nature 609, no. 7929 (September 2022): 1021–28. https://doi.org/10.1038/s41586-022-05215-w.
Hendrikse LD, Haldipur P, Saulnier O, Millman J, Sjoboen AH, Erickson AW, et al. Failure of human rhombic lip differentiation underlies medulloblastoma formation. Nature. 2022 Sep;609(7929):1021–8.
Hendrikse, Liam D., et al. “Failure of human rhombic lip differentiation underlies medulloblastoma formation.” Nature, vol. 609, no. 7929, Sept. 2022, pp. 1021–28. Pubmed, doi:10.1038/s41586-022-05215-w.
Hendrikse LD, Haldipur P, Saulnier O, Millman J, Sjoboen AH, Erickson AW, Ong W, Gordon V, Coudière-Morrison L, Mercier AL, Shokouhian M, Suárez RA, Ly M, Borlase S, Scott DS, Vladoiu MC, Farooq H, Sirbu O, Nakashima T, Nambu S, Funakoshi Y, Bahcheli A, Diaz-Mejia JJ, Golser J, Bach K, Phuong-Bao T, Skowron P, Wang EY, Kumar SA, Balin P, Visvanathan A, Lee JJY, Ayoub R, Chen X, Mungall KL, Luu B, Bérubé P, Wang YC, Pfister SM, Kim S-K, Delattre O, Bourdeaut F, Doz F, Masliah-Planchon J, Grajkowska WA, Loukides J, Dirks P, Fèvre-Montange M, Jouvet A, French PJ, Kros JM, Zitterbart K, Bailey SD, Eberhart CG, Rao AAN, Giannini C, Olson JM, Garami M, Hauser P, Phillips JJ, Ra YS, de Torres C, Mora J, Li KKW, Ng H-K, Poon WS, Pollack IF, López-Aguilar E, Gillespie GY, Van Meter TE, Shofuda T, Vibhakar R, Thompson RC, Cooper MK, Rubin JB, Kumabe T, Jung S, Lach B, Iolascon A, Ferrucci V, de Antonellis P, Zollo M, Cinalli G, Robinson S, Stearns DS, Van Meir EG, Porrati P, Finocchiaro G, Massimino M, Carlotti CG, Faria CC, Roussel MF, Boop F, Chan JA, Aldinger KA, Razavi F, Silvestri E, McLendon RE, Thompson EM, Ansari M, Garre ML, Chico F, Eguía P, Pérezpeña M, Morrissy AS, Cavalli FMG, Wu X, Daniels C, Rich JN, Jones SJM, Moore RA, Marra MA, Huang X, Reimand J, Sorensen PH, Wechsler-Reya RJ, Weiss WA, Pugh TJ, Garzia L, Kleinman CL, Stein LD, Jabado N, Malkin D, Ayrault O, Golden JA, Ellison DW, Doble B, Ramaswamy V, Werbowetski-Ogilvie TE, Suzuki H, Millen KJ, Taylor MD. Failure of human rhombic lip differentiation underlies medulloblastoma formation. Nature. 2022 Sep;609(7929):1021–1028.
Journal cover image

Published In

Nature

DOI

10.1038/s41586-022-05215-w

EISSN

1476-4687

Publication Date

September 2022

Volume

609

Issue

7929

Start / End Page

1021 / 1028

Location

England

Related Subject Headings

  • Transcription Factors
  • T-Box Domain Proteins
  • Repressor Proteins
  • Otx Transcription Factors
  • Mutation
  • Muscle Proteins
  • Metencephalon
  • Medulloblastoma
  • Ki-67 Antigen
  • Humans