Targeting EZH2 in Neuroblastoma
Mentor: Yael Mossé
Indolent neuroblastoma (NB), more often seen in older patients, is often characterized by protracted disease progression and marked by the absence of MYCN amplification. ATRX alterations are the most common recurring event in this indolent clinical subtype and these patients lack effective therapies. ATRX is a SWI/SNF-like chromatin remodeler with diverse roles in chromatin regulation. While the consequences of ATRX alterations on the epigenome have been largely ill-defined, recent work has demonstrated that ATRX in-frame fusion (IFF) proteins lack key chromatin-binding modules and are altered in their genomic binding. ATRX IFFs generate truncated protein products retaining the ATP-dependent helicase domain that no longer bind H3K9me3, and instead are enriched at active promoters, including that of REST. This is in turn postulated to suppress neuronal differentiation, a key feature of neuroblastoma tumors. Recent work has demonstrated that EZH2 inhibition induces upregulation of neuronal maturation genes bound by REST and/or H3K27me3, resulting in apoptosis of ATRX IFF NB cells. ATRX mutations and MYCN amplifications are mutually exclusive genomic alterations found in patients. These genetically distinct NB tumors may develop at different stages of neural crest cell development or arise from different cells of origin, hence being sensitive to EZH2i through different gene expression programs. Thus, the use of EZH2i may be of clinical benefit to NB patients harboring either genetic alteration.
