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ATRX loss predicts poor outcomes and reveals a therapeutic vulnerability to TEAD inhibition in soft tissue sarcomas -- RNA

ABSTRACT: ATRX is an ATP-dependent chromatin remodeler frequently altered in sarcomas and is involved in the maintenance of heterochromatin and transcriptional regulation. Loss of ATRX is associated with aggressive tumor behavior, but the transcriptional mechanisms underlying ATRX-deficient sarcomas remain incompletely understood. In this study, we performed bulk RNA sequencing (RNA-seq) across sarcoma cell lines and genetically engineered cell models with different ATRX backgrounds to characterize transcriptional changes associated with ATRX loss. The dataset includes leiomyosarcoma and liposarcoma cell lines as well as engineered human fibroblast and uterine smooth muscle cell models with perturbations of ATRX and related tumor suppressor genes. Comparative transcriptomic analyses were used to identify ATRX-dependent gene expression programs and transcriptional regulatory pathways. These RNA-seq data complement chromatin accessibility and chromatin profiling experiments and provide a transcriptional framework for understanding how ATRX loss alters regulatory programs in sarcoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE346694 | GEO | 2026/09/21

REPOSITORIES: GEO

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ATRX loss predicts poor outcomes and reveals a therapeutic vulnerability to TEAD inhibition in soft tissue sarcomas

Project description:ATRX is one of the most frequently altered genes in sarcoma and encodes an ATP-dependent chromatin remodeler implicated in maintaining heterochromatin. However, ATRX alterations have not been leveraged for sarcoma treatment. We observed loss of ATRX protein in 14% of soft tissue leiomyosarcoma (STLMS, n =127), 53% of uterine leiomyosarcoma (ULMS, n = 95), 37% of undifferentiated pleomorphic sarcoma (UPS, n = 82), and 8% of dedifferentiated liposarcoma (DDLPS, n = 84). ATRX loss was associated with significantly worse outcomes in ULMS, UPS, and DDLPS. ATRX knockout in sarcoma cells increased proliferation in cooperation with TP53 deletion. ATRX knockout led to chromatin de-repression and enrichment of PRDM4 and NFIX transcription factor (TF) motifs. PRDM4 and NFIX knockdown in ATRX-mutant sarcoma lines resulted in reduced proliferation and invasion suggesting epistatic relationship. Consistent with the known functional relationship between PRMD4 and YAP1, we observed that ATRX/TP53 KO cells were more sensitive to the TEAD inhibitor VT103 compared to TP53 KO and ATRX WT controls. Overall, our results identify ATRX loss as a prognostic factor of worse outcomes, implicate the ATRX-PRDM4-YAP1 axis as a novel underlying mechanism, and suggest use of TEAD inhibition as a potential therapeutic strategy for ATRX-deficient sarcomas.

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ATRX loss predicts poor outcomes and reveals a therapeutic vulnerability to TEAD inhibition in soft tissue sarcomas -- ATAC

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