Failure of human rhombic lip differentiation underlies medulloblastoma formation

Liam D. Hendrikse; Parthiv Haldipur; Olivier Saulnier; Jake Millman; Alexandria H. Sjoboen; Anders W. Erickson; Winnie Ong; Victor Gordon; Ludivine Coudiere-Morrison; Audrey L. Mercier; Mohammad Shokouhian; Raul A. Suarez; Michelle Ly; Stephanie Borlase; David S. Scott; Maria C. Vladoiu; Hamza Farooq; Olga Sirbu; Takuma Nakashima; Shohei Nambu; Yusuke Funakoshi; Alec Bahcheli; J. Javier Diaz-Mejia; Joseph Golser; Kathleen Bach; null Tram Phuong-Bao; Patryk Skowron; Evan Y. Wang; Sachin A. Kumar; Polina Balin; Abhirami Visvanathan; John J. Y. Lee; Ramy Ayoub; Xin Chen; Xiaodi Chen; Karen L. Mungall; Betty Luu; Pierre Berube; Yu C. Wang; Stefan M. Pfister; Seung-Ki Kim; Olivier Delattre; Franck Bourdeaut; Francois Doz; Julien Masliah-Planchon; Wieslawa A. Grajkowska; James Loukides; Peter Dirks; Michelle Fevre-Montange; Anne Jouvet; Pim J. French; Johan M. Kros; Karel Zitterbart; Swneke D. Bailey; Charles G. Eberhart; Amulya A. N. Rao; Caterina Giannini; James M. Olson; Miklos Garami; Peter Hauser; Joanna J. Phillips; Young S. Ra; Carmen de Torres; Jaume Mora; Kay K. W. Li; Ho-Keung Ng; Wai S. Poon; Ian F. Pollack; Enrique Lopez-Aguilar; G. Yancey Gillespie; Timothy E. Van Meter; Tomoko Shofuda; Rajeev Vibhakar; Reid C. Thompson; Michael K. Cooper; Joshua B. Rubin; Toshihiro Kumabe; Shin Jung; Boleslaw Lach; Achille Lolascon; Veronica Ferrucci; Pasqualino de Antonellis; Massimo Zollo; Giuseppe Cinalli; Shenandoah Robinson; Duncan S. Stearns; Erwin G. Van Meir; Paola Porrati; Gaetano Finocchiaro; Maura Massimino; Carlos G. Carlotti; Claudia C. Faria; Martine F. Roussel; Frederick Boop; Jennifer A. Chan; Kimberly A. Aldinger; Ferechte Razavi; Evelina Silvestri; Roger E. McLendon; Eric M. Thompson; Marc Ansari; Maria L. Garre; Fernando Chico; Pilar Eguia; Mario Perezpena; A. Sorana Morrissy; Florence M. G. Cavalli; Xiaochong Wu; Craig Daniels; Jeremy N. Rich; Steven J. M. Jones; Richard A. Moore; Marco A. Marra; Xi Huang; Juri Reimand; Poul H. Sorensen; Robert J. Wechsler-Reya; William A. Weiss; Trevor J. Pugh; Livia Garzia; Claudia L. Kleinman; Lincoln D. Stein; Nada Jabado; David Malkin; Olivier Ayrault; Jeffrey A. Golden; David W. Ellison; Brad Doble; Vijay Ramaswamy; Tamra E. Werbowetski-Ogilvie; Hiromichi Suzuki; Kathleen J. Millen; Michael D. Taylor

doi:10.1038/s41586-022-05215-w

Failure of human rhombic lip differentiation underlies medulloblastoma formation

Liam D. Hendrikse, Parthiv Haldipur, Olivier Saulnier, Jake Millman, Alexandria H. Sjoboen, Anders W. Erickson, Winnie Ong, Victor Gordon, Ludivine Coudiere-Morrison, Audrey L. Mercier, Mohammad Shokouhian, Raul A. Suarez, Michelle Ly, Stephanie Borlase, David S. Scott, Maria C. Vladoiu, Hamza Farooq, Olga Sirbu, Takuma Nakashima, Shohei NambuYusuke Funakoshi, Alec Bahcheli, J. Javier Diaz-Mejia, Joseph Golser, Kathleen Bach, Tram Phuong-Bao, Patryk Skowron, Evan Y. Wang, Sachin A. Kumar, Polina Balin, Abhirami Visvanathan, John J. Y. Lee, Ramy Ayoub, Xin Chen, Xiaodi Chen, Karen L. Mungall, Betty Luu, Pierre Berube, Yu C. Wang, Stefan M. Pfister, Seung-Ki Kim, Olivier Delattre, Franck Bourdeaut, Francois Doz, Julien Masliah-Planchon, Wieslawa A. Grajkowska, James Loukides, Peter Dirks, Michelle Fevre-Montange, Anne Jouvet, Pim J. French, Johan M. Kros, Karel Zitterbart, Swneke D. Bailey, Charles G. Eberhart, Amulya A. N. Rao, Caterina Giannini, James M. Olson, Miklos Garami, Peter Hauser, Joanna J. Phillips, Young S. Ra, Carmen de Torres, Jaume Mora, Kay K. W. Li, Ho-Keung Ng, Wai S. Poon, Ian F. Pollack, Enrique Lopez-Aguilar, G. Yancey Gillespie, Timothy E. Van Meter, Tomoko Shofuda, Rajeev Vibhakar, Reid C. Thompson, Michael K. Cooper, Joshua B. Rubin, Toshihiro Kumabe, Shin Jung, Boleslaw Lach, Achille Lolascon, Veronica Ferrucci, Pasqualino de Antonellis, Massimo Zollo, Giuseppe Cinalli, Shenandoah Robinson, Duncan S. Stearns, Erwin G. Van Meir, Paola Porrati, Gaetano Finocchiaro, Maura Massimino, Carlos G. Carlotti, Claudia C. Faria, Martine F. Roussel, Frederick Boop, Jennifer A. Chan, Kimberly A. Aldinger, Ferechte Razavi, Evelina Silvestri, Roger E. McLendon, Eric M. Thompson, Marc Ansari, Maria L. Garre, Fernando Chico, Pilar Eguia, Mario Perezpena, A. Sorana Morrissy, Florence M. G. Cavalli, Xiaochong Wu, Craig Daniels, Jeremy N. Rich, Steven J. M. Jones, Richard A. Moore, Marco A. Marra, Xi Huang, Juri Reimand, Poul H. Sorensen, Robert J. Wechsler-Reya, William A. Weiss, Trevor J. Pugh, Livia Garzia, Claudia L. Kleinman, Lincoln D. Stein, Nada Jabado, David Malkin, Olivier Ayrault, Jeffrey A. Golden, David W. Ellison, Brad Doble, Vijay Ramaswamy, Tamra E. Werbowetski-Ogilvie, Hiromichi Suzuki, Kathleen J. Millen, Michael D. Taylor^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

64 Citations (Scopus)

Abstract

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to 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, mutations that activate WNT signalling lead to WNT MB in the lower RL ^9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage ^3,4. 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.

Original language	English
Pages (from-to)	1021-1028
Number of pages	8
Journal	Nature
Volume	609
Issue number	7929
Early online date	21 Sept 2022
DOIs	https://doi.org/10.1038/s41586-022-05215-w
Publication status	Published - 29 Sept 2022

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10.1038/s41586-022-05215-w

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10026724

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Hendrikse, L. D., Haldipur, P., Saulnier, O., Millman, J., Sjoboen, A. H., Erickson, A. W., Ong, W., Gordon, V., Coudiere-Morrison, L., Mercier, A. L., Shokouhian, M., Suarez, R. A., Ly, M., Borlase, S., Scott, D. S., Vladoiu, M. C., Farooq, H., Sirbu, O., Nakashima, T., ... 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

@article{50e17f8e09f74a459235c0693bf63ccc,

title = "Failure of human rhombic lip differentiation underlies medulloblastoma formation",

abstract = "Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to 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, mutations that activate WNT signalling lead to WNT MB in the lower RL 9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage 3,4. 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.",

author = "Hendrikse, {Liam D.} and Parthiv Haldipur and Olivier Saulnier and Jake Millman and Sjoboen, {Alexandria H.} and Erickson, {Anders W.} and Winnie Ong and Victor Gordon and Ludivine Coudiere-Morrison and Mercier, {Audrey L.} and Mohammad Shokouhian and Suarez, {Raul A.} and Michelle Ly and Stephanie Borlase and Scott, {David S.} and Vladoiu, {Maria C.} and Hamza Farooq and Olga Sirbu and Takuma Nakashima and Shohei Nambu and Yusuke Funakoshi and Alec Bahcheli and Diaz-Mejia, {J. Javier} and Joseph Golser and Kathleen Bach and {Tram Phuong-Bao} and Patryk Skowron and Wang, {Evan Y.} and Kumar, {Sachin A.} and Polina Balin and Abhirami Visvanathan and Lee, {John J. Y.} and Ramy Ayoub and Xin Chen and Xiaodi Chen and Mungall, {Karen L.} and Betty Luu and Pierre Berube and Wang, {Yu C.} and Pfister, {Stefan M.} and Seung-Ki Kim and Olivier Delattre and Franck Bourdeaut and Francois Doz and Julien Masliah-Planchon and Grajkowska, {Wieslawa A.} and James Loukides and Peter Dirks and Michelle Fevre-Montange and Anne Jouvet and French, {Pim J.} and Kros, {Johan M.} and Karel Zitterbart and Bailey, {Swneke D.} and Eberhart, {Charles G.} and Rao, {Amulya A. N.} and Caterina Giannini and Olson, {James M.} and Miklos Garami and Peter Hauser and Phillips, {Joanna J.} and Ra, {Young S.} and {de Torres}, Carmen and Jaume Mora and Li, {Kay K. W.} and Ho-Keung Ng and Poon, {Wai S.} and Pollack, {Ian F.} and Enrique Lopez-Aguilar and Gillespie, {G. Yancey} and {Van Meter}, {Timothy E.} and Tomoko Shofuda and Rajeev Vibhakar and Thompson, {Reid C.} and Cooper, {Michael K.} and Rubin, {Joshua B.} and Toshihiro Kumabe and Shin Jung and Boleslaw Lach and Achille Lolascon and Veronica Ferrucci and {de Antonellis}, Pasqualino and Massimo Zollo and Giuseppe Cinalli and Shenandoah Robinson and Stearns, {Duncan S.} and {Van Meir}, {Erwin G.} and Paola Porrati and Gaetano Finocchiaro and Maura Massimino and Carlotti, {Carlos G.} and Faria, {Claudia C.} and Roussel, {Martine F.} and Frederick Boop and Chan, {Jennifer A.} and Aldinger, {Kimberly A.} and Ferechte Razavi and Evelina Silvestri and McLendon, {Roger E.} and Thompson, {Eric M.} and Marc Ansari and Garre, {Maria L.} and Fernando Chico and Pilar Eguia and Mario Perezpena and Morrissy, {A. Sorana} and Cavalli, {Florence M. G.} and Xiaochong Wu and Craig Daniels and Rich, {Jeremy N.} and Jones, {Steven J. M.} and Moore, {Richard A.} and Marra, {Marco A.} and Xi Huang and Juri Reimand and Sorensen, {Poul H.} and Wechsler-Reya, {Robert J.} and Weiss, {William A.} and Pugh, {Trevor J.} and Livia Garzia and Kleinman, {Claudia L.} and Stein, {Lincoln D.} and Nada Jabado and David Malkin and Olivier Ayrault and Golden, {Jeffrey A.} and Ellison, {David W.} and Brad Doble and Vijay Ramaswamy and Werbowetski-Ogilvie, {Tamra E.} and Hiromichi Suzuki and Millen, {Kathleen J.} and Taylor, {Michael D.}",

year = "2022",

month = sep,

day = "29",

doi = "10.1038/s41586-022-05215-w",

language = "English",

volume = "609",

pages = "1021--1028",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

number = "7929",

}

Hendrikse, LD, Haldipur, P, Saulnier, O, Millman, J, Sjoboen, AH, Erickson, AW, Ong, W, Gordon, V, Coudiere-Morrison, L, Mercier, AL, Shokouhian, M, Suarez, 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, Tram Phuong-Bao, Skowron, P, Wang, EY, Kumar, SA, Balin, P, Visvanathan, A, Lee, JJY, Ayoub, R, Chen, X, Chen, X, Mungall, KL, Luu, B, Berube, P, Wang, YC, Pfister, SM, Kim, S-K, Delattre, O, Bourdeaut, F, Doz, F, Masliah-Planchon, J, Grajkowska, WA, Loukides, J, Dirks, P, Fevre-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, Lopez-Aguilar, E, Gillespie, GY, Van Meter, TE, Shofuda, T, Vibhakar, R, Thompson, RC, Cooper, MK, Rubin, JB, Kumabe, T, Jung, S, Lach, B, Lolascon, 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, Eguia, P, Perezpena, 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 2022, 'Failure of human rhombic lip differentiation underlies medulloblastoma formation', Nature, vol. 609, no. 7929, pp. 1021-1028. https://doi.org/10.1038/s41586-022-05215-w

TY - JOUR

T1 - Failure of human rhombic lip differentiation underlies medulloblastoma formation

AU - Hendrikse, Liam D.

AU - Haldipur, Parthiv

AU - Saulnier, Olivier

AU - Millman, Jake

AU - Sjoboen, Alexandria H.

AU - Erickson, Anders W.

AU - Ong, Winnie

AU - Gordon, Victor

AU - Coudiere-Morrison, Ludivine

AU - Mercier, Audrey L.

AU - Shokouhian, Mohammad

AU - Suarez, Raul A.

AU - Ly, Michelle

AU - Borlase, Stephanie

AU - Scott, David S.

AU - Vladoiu, Maria C.

AU - Farooq, Hamza

AU - Sirbu, Olga

AU - Nakashima, Takuma

AU - Nambu, Shohei

AU - Funakoshi, Yusuke

AU - Bahcheli, Alec

AU - Diaz-Mejia, J. Javier

AU - Golser, Joseph

AU - Bach, Kathleen

AU - Tram Phuong-Bao, null

AU - Skowron, Patryk

AU - Wang, Evan Y.

AU - Kumar, Sachin A.

AU - Balin, Polina

AU - Visvanathan, Abhirami

AU - Lee, John J. Y.

AU - Ayoub, Ramy

AU - Chen, Xin

AU - Chen, Xiaodi

AU - Mungall, Karen L.

AU - Luu, Betty

AU - Berube, Pierre

AU - Wang, Yu C.

AU - Pfister, Stefan M.

AU - Kim, Seung-Ki

AU - Delattre, Olivier

AU - Bourdeaut, Franck

AU - Doz, Francois

AU - Masliah-Planchon, Julien

AU - Grajkowska, Wieslawa A.

AU - Loukides, James

AU - Dirks, Peter

AU - Fevre-Montange, Michelle

AU - Jouvet, Anne

AU - French, Pim J.

AU - Kros, Johan M.

AU - Zitterbart, Karel

AU - Bailey, Swneke D.

AU - Eberhart, Charles G.

AU - Rao, Amulya A. N.

AU - Giannini, Caterina

AU - Olson, James M.

AU - Garami, Miklos

AU - Hauser, Peter

AU - Phillips, Joanna J.

AU - Ra, Young S.

AU - de Torres, Carmen

AU - Mora, Jaume

AU - Li, Kay K. W.

AU - Ng, Ho-Keung

AU - Poon, Wai S.

AU - Pollack, Ian F.

AU - Lopez-Aguilar, Enrique

AU - Gillespie, G. Yancey

AU - Van Meter, Timothy E.

AU - Shofuda, Tomoko

AU - Vibhakar, Rajeev

AU - Thompson, Reid C.

AU - Cooper, Michael K.

AU - Rubin, Joshua B.

AU - Kumabe, Toshihiro

AU - Jung, Shin

AU - Lach, Boleslaw

AU - Lolascon, Achille

AU - Ferrucci, Veronica

AU - de Antonellis, Pasqualino

AU - Zollo, Massimo

AU - Cinalli, Giuseppe

AU - Robinson, Shenandoah

AU - Stearns, Duncan S.

AU - Van Meir, Erwin G.

AU - Porrati, Paola

AU - Finocchiaro, Gaetano

AU - Massimino, Maura

AU - Carlotti, Carlos G.

AU - Faria, Claudia C.

AU - Roussel, Martine F.

AU - Boop, Frederick

AU - Chan, Jennifer A.

AU - Aldinger, Kimberly A.

AU - Razavi, Ferechte

AU - Silvestri, Evelina

AU - McLendon, Roger E.

AU - Thompson, Eric M.

AU - Ansari, Marc

AU - Garre, Maria L.

AU - Chico, Fernando

AU - Eguia, Pilar

AU - Perezpena, Mario

AU - Morrissy, A. Sorana

AU - Cavalli, Florence M. G.

AU - Wu, Xiaochong

AU - Daniels, Craig

AU - Rich, Jeremy N.

AU - Jones, Steven J. M.

AU - Moore, Richard A.

AU - Marra, Marco A.

AU - Huang, Xi

AU - Reimand, Juri

AU - Sorensen, Poul H.

AU - Wechsler-Reya, Robert J.

AU - Weiss, William A.

AU - Pugh, Trevor J.

AU - Garzia, Livia

AU - Kleinman, Claudia L.

AU - Stein, Lincoln D.

AU - Jabado, Nada

AU - Malkin, David

AU - Ayrault, Olivier

AU - Golden, Jeffrey A.

AU - Ellison, David W.

AU - Doble, Brad

AU - Ramaswamy, Vijay

AU - Werbowetski-Ogilvie, Tamra E.

AU - Suzuki, Hiromichi

AU - Millen, Kathleen J.

AU - Taylor, Michael D.

PY - 2022/9/29

Y1 - 2022/9/29

N2 - Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to 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, mutations that activate WNT signalling lead to WNT MB in the lower RL 9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage 3,4. 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.

AB - Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to 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, mutations that activate WNT signalling lead to WNT MB in the lower RL 9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage 3,4. 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.

UR - http://www.scopus.com/inward/record.url?scp=85138487209&partnerID=8YFLogxK

U2 - 10.1038/s41586-022-05215-w

DO - 10.1038/s41586-022-05215-w

M3 - Article

SN - 0028-0836

VL - 609

SP - 1021

EP - 1028

JO - Nature

JF - Nature

IS - 7929

ER -

Failure of human rhombic lip differentiation underlies medulloblastoma formation

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