Combined MYC and P53 defects emerge at medulloblastoma relapse and define rapidly progressive, therapeutically targetable disease.

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 and Clifford, Steven C (2015) Combined MYC and P53 defects emerge at medulloblastoma relapse and define rapidly progressive, therapeutically targetable disease. Cancer cell, 27 (1). pp. 72-84. ISSN 1878-3686

[img]
Preview
PDF
2015 Combined MYC and P53 Defects Emerge at Medulloblastoma Relapse and Define Rapidly Progressive Therapeutically Targetable Disease extended.pdf - Published Version
Available under License Creative Commons Attribution Non-commercial No Derivatives.

Download (11MB) | Preview

Search Google Scholar

Abstract

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.

Item Type: Article
Subjects: Sciences > Biomedical Sciences
Sciences > Health Sciences
Divisions: Faculty of Health Sciences and Wellbeing > School of Medicine
Depositing User: Kevin Petrie
Date Deposited: 18 Aug 2020 18:12
Last Modified: 19 Aug 2020 09:39
URI: http://sure.sunderland.ac.uk/id/eprint/12437
ORCID for Kevin Petrie: ORCID iD orcid.org/0000-0002-9805-9152

Actions (login required)

View Item View Item

Downloads

Downloads per month over past year