ATRX in-frame fusion neuroblastoma is sensitive to EZH2 inhibition via modulation of neuronal gene signatures Journal Article


Authors: Qadeer, Z. A.; Valle-Garcia, D.; Hasson, D.; Sun, Z.; Cook, A.; Nguyen, C.; Soriano, A.; Ma, A.; Griffiths, L. M.; Zeineldin, M.; Filipescu, D.; Jubierre, L.; Chowdhury, A.; Deevy, O.; Chen, X.; Finkelstein, D. B.; Bahrami, A.; Stewart, E.; Federico, S.; Gallego, S.; Dekio, F.; Fowkes, M.; Meni, D.; Maris, J. M.; Weiss, W. A.; Roberts, S. S.; Cheung, N. K. V.; Jin, J.; Segura, M. F.; Dyer, M. A.; Bernstein, E.
Article Title: ATRX in-frame fusion neuroblastoma is sensitive to EZH2 inhibition via modulation of neuronal gene signatures
Abstract: Qadeer et al. show that ATRX in-frame fusions (IFF), found in a subset of neuroblastomas, are redistributed from wild-type ATRX-binding sites to other genomic regions, including the REST promoter. REST expression silences neuronal differentiation genes, which can be derepressed with EZH2 inhibitors to suppress ATRX IFF cell growth. © 2019 Elsevier Inc. ATRX alterations occur at high frequency in neuroblastoma of adolescents and young adults. Particularly intriguing are the large N-terminal deletions of ATRX (Alpha Thalassemia/Mental Retardation, X-linked) that generate in-frame fusion (IFF) proteins devoid of key chromatin interaction domains, while retaining the SWI/SNF-like helicase region. We demonstrate that ATRX IFF proteins are redistributed from H3K9me3-enriched chromatin to promoters of active genes and identify REST as an ATRX IFF target whose activation promotes silencing of neuronal differentiation genes. We further show that ATRX IFF cells display sensitivity to EZH2 inhibitors, due to derepression of neurogenesis genes, including a subset of REST targets. Taken together, we demonstrate that ATRX structural alterations are not loss-of-function and put forward EZH2 inhibitors as a potential therapy for ATRX IFF neuroblastoma. © 2019 Elsevier Inc.
Keywords: controlled study; unclassified drug; human cell; promoter region; cell survival; complex formation; carboxy terminal sequence; transcription factor; neuromodulation; protein interaction; tumor xenograft; neuroblastoma; messenger rna; gene fusion; telomerase reverse transcriptase; gene silencing; nerve cell differentiation; loss of function mutation; nervous system development; copy number variation; transcription factor ezh2; neuronal differentiation; neuroectoderm; ezh2; gene ontology; atrx; human; female; priority journal; article; rest; tazemetostat; transcriptional regulator atrx; epigenetic therapeutics; re 1 silencing transcription factor; la-n-6 cell line; sk-n-fi cell line
Journal Title: Cancer Cell
Volume: 36
Issue: 5
ISSN: 1535-6108
Publisher: Cell Press  
Date Published: 2019-11-11
Start Page: 512
End Page: 527.e9
Language: English
DOI: 10.1016/j.ccell.2019.09.002
PUBMED: 31631027
PROVIDER: scopus
PMCID: PMC6851493
DOI/URL:
Notes: Source: Scopus
Altmetric
Citation Impact
MSK Authors
  1. Nai-Kong Cheung
    515 Cheung
  2. Stephen Stacy Roberts
    61 Roberts
  3. David Meni
    2 Meni