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ATRX In-Frame Fusion Neuroblastoma Is Sensitive to EZH2 Inhibition via Modulation of Neuronal Gene Signatures
Zulekha A Qadeer1, David Valle-Garcia2, Dan Hasson2
1Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Departments of Neurology, Neurosurgery, and Pediatrics, University of California, San Francisco, San Francisco, CA 94158, USA.
Altered Alpha Thalassemia/Mental Retardation, X-linked (ATRX) proteins in neuroblastoma activate REST, silencing neuronal genes. EZH2 inhibitors show promise for treating this specific neuroblastoma subtype.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- High frequency of ATRX alterations in adolescent and young adult neuroblastoma.
- Focus on large N-terminal deletions creating in-frame fusion (IFF) proteins.
Purpose of the Study:
- Investigate the functional consequences of ATRX IFF proteins.
- Identify therapeutic strategies for ATRX IFF neuroblastoma.
Main Methods:
- Chromatin immunoprecipitation assays.
- Gene expression analysis.
- Cellular sensitivity assays.
Main Results:
- ATRX IFF proteins redistribute to active gene promoters.
- REST is identified as a target, leading to neuronal gene silencing.
- ATRX IFF cells exhibit sensitivity to EZH2 inhibitors due to neurogenesis gene derepression.
Conclusions:
- ATRX structural alterations are not simple loss-of-function.
- EZH2 inhibitors represent a potential therapeutic avenue for ATRX IFF neuroblastoma.
