ATRX In-Frame Fusion Neuroblastoma Is Sensitive to EZH2 Inhibition via Modulation of Neuronal Gene Signatures
Por:
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.
Publicada:
1 ene 2019
Resumen:
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.
Filiaciones:
Qadeer Z.A.:
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
Departments of Neurology, Neurosurgery, and Pediatrics, University of California, San Francisco, San Francisco, CA 94158, United States
Valle-Garcia D.:
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
Hasson D.:
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
Sun Z.:
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
Cook A.:
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
Nguyen C.:
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
Soriano A.:
Laboratory of Translational Research in Child and Adolescent Cancer, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, 08035, Spain
Ma A.:
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
Griffiths L.M.:
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, United States
Zeineldin M.:
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, United States
Filipescu D.:
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
Jubierre L.:
Laboratory of Translational Research in Child and Adolescent Cancer, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, 08035, Spain
Chowdhury A.:
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
Deevy O.:
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
Chen X.:
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, United States
Finkelstein D.B.:
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, United States
Bahrami A.:
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, United States
Stewart E.:
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, United States
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, United States
Federico S.:
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, United States
Gallego S.:
Pediatric Oncology and Hematology Department, University Hospital Vall d'Hebron, Barcelona, 08035, Spain
Dekio F.:
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
Fowkes M.:
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
Meni D.:
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, United States
Maris J.M.:
Center for Childhood Cancer Research at the Children's Hospital of Philadelphia, Perlman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, United States
Weiss W.A.:
Departments of Neurology, Neurosurgery, and Pediatrics, University of California, San Francisco, San Francisco, CA 94158, United States
Roberts S.S.:
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, United States
Cheung N.-K.V.:
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, United States
Jin J.:
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
Segura M.F.:
Laboratory of Translational Research in Child and Adolescent Cancer, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, 08035, Spain
Dyer M.A.:
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, United States
Bernstein E.:
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
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