# Mechanisms and modeling of neuroblastoma-associated ATRX alterations

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $400,966

## Abstract

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.

## Key facts

- **NIH application ID:** 10320955
- **Project number:** 5R01NS110837-03
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Emily Bernstein
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $400,966
- **Award type:** 5
- **Project period:** 2020-03-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10320955

## Citation

> US National Institutes of Health, RePORTER application 10320955, Mechanisms and modeling of neuroblastoma-associated ATRX alterations (5R01NS110837-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10320955. Licensed CC0.

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