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ATRX mutations mediate an immunogenic phenotype and macrophage infiltration in neuroblastoma.

ABSTRACT: ATRX is one of the most frequently mutated genes in high-risk neuroblastoma. ATRX mutations are mutually exclusive with MYCN amplification and mark a recognizable patient subgroup, presenting in older children with chemotherapy-resistant, slowly progressive disease. The mechanisms underlying how ATRX mutations drive high-risk and difficult-to-treat neuroblastoma are still largely elusive. To unravel the role of ATRX in neuroblastoma, we generated isogenic neuroblastoma cell line models of both ATRX loss of-function and ATRX in-frame multi-exon deletions, representing different types of alterations found in patients. RNA-sequencing analysis consistently showed significant upregulation of pathways implicated in inflammatory responses and epithelial-to- mesenchymal transition in the ATRX-mutant cell lines. In vivo, ATRX mutations mediate macrophage recruitment in xenograft models. This was further confirmed in patient-derived xenograft models. In support of this, bioinformatic analysis of previously published neuroblastoma patient data sets revealed an immunogenic phenotype and higher score of macrophages (with no distinction between M1 and M2 macrophage populations) and dendritic cells, but not lymphocytes, in ATRX-mutant versus ATRX wildtype tumors. Histopathological assessment of diagnostic samples from patients with ATRX mutant disease confirmed these findings with more macrophage infiltration compared to MYCN-amplified tumors. In conclusion, these results highlight that in contrast to MYCN-amplified neuroblastoma, which is associated with a cold immune microenvironment, ATRX-mutated neuroblastoma is characterized by a distinct immunogenic phenotype.

ORGANISM(S): Homo sapiens

PROVIDER: GSE277158 | GEO | 2025/02/10

REPOSITORIES: GEO

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