Onco-histones: molecular drivers of paediatric brain cancers

Host: Prof. Leonie Quinn

Abstract

Survivorship for various cancers has increased significantly over the last 30 years, while outcomes for brain cancer patients remain dismal. In Australia, brain cancers constitute a leading cause of cancer-related mortality in children. My research program addresses the urgent need to improve outcomes for patients facing a brain cancer diagnosis, in particular, those suffering from paediatric glioblastoma, a fatal childhood brain cancer with a 5-year survival of 20%.

One striking finding in the area of cancer epigenetics has been the identification of the mutations of histone H3.3 (onco-histone) and chromatin remodeller ATRX genes in paediatric glioblastoma. My group has shown that mutated H3.3 disrupts the genome-wide chromatin state by inhibiting KDM4 histone demethylase in paediatric glioblastomas, and identified KDM4B as a key regulator of Alternative Lengthening of Telomere (ALT) telomere maintenance pathway that drives cellular immortality in these cancers. We have also shown that ATRX/H3.3-mutated cancers suffer a severe ribosomal DNA repeat instability and loss, rendering them sensitive to treatment with RNA Polymerase I drugs. Here, I will discuss our recent discoveries on chromatin abnormalities associated with onco-histones in paediatric glioblastomas and molecular mechanism underlying the ALT telomere maintenance pathway.

Biography

A/Prof Lee Wong is the Group Leader of the Epigenetics and Chromatin Research Lab at Monash University. She has 20 years of experience working in the chromatin field, especially on telomere biology and histone mutations (onco-histones) in cancer. Her research program aims to define telomere and chromatin defects linked to the development of paediatric brain cancers, and to provide potential translatable opportunities for treatment of these tumours. Her work was the first to report the roles for histone H3.3 and chromatin remodeller ATRX in protecting the telomeres and controlling genome integrity. Her work paved the way to studies that have linked ATRX mutations to Alternative Lengthening of Telomere (ALT), which is a key telomere maintenance mechanism activated in human cancers to evade telomere loss. Her recent study has identified new factors that control the ALT pathway, elucidating the hidden molecular mechanism that controls cell immortality, and solving a longstanding key question in the telomere and cancer fields.