Details

Autor(en) / Beteiligte

• Hill, Rebecca M.
• Kuijper, Sanne
• Lindsey, Janet C.
• Petrie, Kevin
• Schwalbe, Ed C.
• Barker, Karen
• Boult, Jessica K.R.
• Williamson, Daniel
• Ahmad, Zai
• Hallsworth, Albert
• Ryan, Sarra L.
• Poon, Evon
• Robinson, Simon P.
• Ruddle, Ruth
• Raynaud, Florence I.
• Howell, Louise
• Kwok, Colin
• Joshi, Abhijit
• Nicholson, Sarah Leigh
• Crosier, Stephen
• Ellison, David W.
• Wharton, Stephen B.
• Robson, Keith
• Michalski, Antony
• Hargrave, Darren
• Jacques, Thomas S.
• Pizer, Barry
• Bailey, Simon
• Swartling, Fredrik J.
• Weiss, William A.
• Chesler, Louis
• Clifford, Steven C.

Titel

Combined MYC and P53 Defects Emerge at Medulloblastoma Relapse and Define Rapidly Progressive, Therapeutically Targetable Disease

Ist Teil von

• Cancer cell, 2015-01, Vol.27 (1), p.72-84

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2015

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• We undertook a comprehensive clinical and biological investigation of serial medulloblastoma biopsies obtained at diagnosis and relapse. Combined MYC family amplifications and P53 pathway defects commonly emerged at relapse, and all patients in this group died of rapidly progressive disease postrelapse. To study this interaction, we investigated a transgenic model of MYCN-driven medulloblastoma and found spontaneous development of Trp53 inactivating mutations. Abrogation of p53 function in this model produced aggressive tumors that mimicked characteristics of relapsed human tumors with combined P53-MYC dysfunction. Restoration of p53 activity and genetic and therapeutic suppression of MYCN all reduced tumor growth and prolonged survival. Our findings identify P53-MYC interactions at medulloblastoma relapse as biomarkers of clinically aggressive disease that may be targeted therapeutically. [Display omitted] •Combined P53 and MYC family defects emerge at medulloblastoma relapse•P53-MYC defects are a biomarker for rapidly progressive relapsed disease•Trp53 and MYCN interact to drive aggressive medulloblastoma development in mice•Targeting MYCN or P53 pathway reactivation reduces tumor growth and prolongs survival Hill et al. find that coincident MYC amplifications and p53 pathway defects are common in relapsed medulloblastoma (MB) and correlate with poor postrelapse prognosis. The authors go on to explore this MYC-p53 interaction in a mouse MB model and show that these tumors are dependent on both aberrations.