PROJECT SUMMARY Epigenetic deregulation is now widely accepted as a hallmark of pediatric cancer. Mutations and structural alterations of the SWI/SNF-like chromatin remodeler ATRX (Alpha Thalassemia/Mental Retardation, X- linked) have been reported at high frequency in a number of adult and pediatric tumors. However, the consequences of ATRX mutations in cancer and their underlying epigenetic sensitivities remain ill defined. Particularly intriguing are the large N-terminal deletions of ATRX in neuroblastoma (NB) found in older children and adolescents that generate in-frame fusion (IFF) proteins devoid of key chromatin interaction modules. Our preliminary data suggests that NB cells harboring ATRX IFFs have distinct gene expression programs compared to WT ATRX NB cells. This is due in part to H3K27me3-mediated silencing of REST (RE1 Silencing Transcription Factor) target genes involved in neuronal differentiation. In turn, we find that ATRX IFF cells display sensitivity to EZH2 inhibition (EZH2i) in vitro and in vivo. However, the role of ATRX IFFs in indolent NB remains poorly understood. In order to decipher the underlying mechanisms of neuronal gene silencing in ATRX IFF NB, and how to alleviate it and induce cell death, we will determine the role of ATRX IFF proteins in promoting NB development through functional, epigenomic and proteomic studies (AIM 1), and define NB transcriptomes and EZH2/H3K27me3/REST target genes in NB cells +/- EZH2i (AIM 2). These integrated epigenomic, proteomic and transcriptional studies will reveal the consequences of ATRX structural alterations in NB in development and provide rationale for EZH2 inhibition as a strategy to treat ATRX-altered NB.
|Effective start/end date||1/03/20 → 31/12/23|
- National Institute of Neurological Disorders and Stroke: $360,869.00
- National Institute of Neurological Disorders and Stroke: $417,299.00
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