{"doi":"10.1016/j.ebiom.2020.103000","title":"A strike against indolent neuroblastoma","abstract":"Neuroblastoma has extraordinary diversity in its presentation and clinical course, and prognosis is often associated with age of diagnosis. Younger children tend to have better outcomes, where spontaneous regression can be observed without any therapeutic intervention [[1]Evans A.E. D'Angio G.J. Randolph J A proposed staging for children with neuroblastoma. Children's cancer study group A.Cancer. 1971; 27: 374-378Crossref PubMed Scopus (831) Google Scholar]. In contrast, indolent or chronic neuroblastoma in older children and adolescents is characterized by protracted disease that is refractory to chemotherapy [[2]Mossé Y.P.P. Deyell R.J. Berthold F. Nagakawara A. Ambros P.F. Monclair T. et al.Neuroblastoma in older children, adolescents and young adults: a report from the International Neuroblastoma Risk Group project.Pediatr Blood Cancer. 2014; 61: 627-635Crossref PubMed Scopus (49) Google Scholar]. Alterations of the chromatin remodeler ATRX are the most common recurrent event in this indolent clinical subtype, which is associated with overall poor survival and lacks effective therapies [[3]Cheung N.-.K.V.K. Zhang J. Lu C. Parker M. Bahrami A. Tickoo S.K. et al.Association of age at diagnosis and genetic mutations in patients with neuroblastoma.JAMA. 2012; 307: 1062-1071Crossref PubMed Scopus (259) Google Scholar,[4]Molenaar J.J. Koster J. Zwijnenburg D.A. van Sluis P. Valentijn L.J. van der Ploeg I. et al.Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes.Nature. 2012; 483: 589Crossref PubMed Scopus (569) Google Scholar]. In this article of EBioMedicine, George et al. utilize an isogenic cellular system to screen for compounds that target ATRX-deficient neuroblastoma [[5]George S.L. Lorenzi F. King D. Hart S. Campbell J. Pemberton H. et al.Therapeutic vulnerabilities in the DNA damage response for the treatment of ATRX mutant neuroblastoma.EBioMedicine. 2020; https://doi.org/10.1016/j.ebiom.2020.102971Summary Full Text Full Text PDF PubMed Scopus (9) Google Scholar]. Their study sheds light on a promising therapeutic strategy consisting of a combination of olaparib (a PARP inhibitor) and irinotecan (a topoisomerase I inhibitor), both clinical compounds. ATRX mutations were first identified in neuroblastoma in 2012 through genome sequencing efforts [[3]Cheung N.-.K.V.K. Zhang J. Lu C. Parker M. Bahrami A. Tickoo S.K. et al.Association of age at diagnosis and genetic mutations in patients with neuroblastoma.JAMA. 2012; 307: 1062-1071Crossref PubMed Scopus (259) Google Scholar,[4]Molenaar J.J. Koster J. Zwijnenburg D.A. van Sluis P. Valentijn L.J. van der Ploeg I. et al.Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes.Nature. 2012; 483: 589Crossref PubMed Scopus (569) Google Scholar]. Approximately 30–40% of tumours in older children harbour ATRX alterations, half of which are point mutations leading to loss of ATRX product, and the other half comprise large deletions of the amino terminal chromatin binding modules creating an in-frame fusion protein [[3]Cheung N.-.K.V.K. Zhang J. Lu C. Parker M. Bahrami A. Tickoo S.K. et al.Association of age at diagnosis and genetic mutations in patients with neuroblastoma.JAMA. 2012; 307: 1062-1071Crossref PubMed Scopus (259) Google Scholar,[6]Qadeer Z.A. Valle-Garcia D. Hasson D. Sun Z. Cook A. Nguyen C. et al.ATRX In-Frame Fusion Neuroblastoma Is Sensitive to EZH2 Inhibition via Modulation of Neuronal Gene Signatures.Cancer Cell. 2019; Summary Full Text Full Text PDF PubMed Scopus (17) Google Scholar]. ATRX plays a role in a myriad of nuclear processes, ranging from its role in histone variant deposition [[7]Dyer M.A. Qadeer Z.A. Valle-Garcia D. Bernstein E ATRX and DAXX: mechanisms and Mutations.Cold Spring Harb Perspect Med. 2017; 7Crossref PubMed Scopus (61) Google Scholar] to maintenance of genome stability. This includes the regulation of repetitive DNA such as pericentric and telomeric heterochromatin [","journal":"EBioMedicine","year":2020,"id":116930,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9563,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":329958,"name":"Emily Bernstein","orcid":"0000-0001-6533-8326","position":1,"is_corresponding":false},{"id":546414,"name":"April Cook","orcid":null,"position":0,"is_corresponding":true}],"reference_count":10,"raw_metadata":null,"created_at":"2026-07-18T23:13:47.803267Z","pmid":"32977162","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}