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ATRX loss predicts poor outcomes and reveals a therapeutic vulnerability to TEAD inhibition in soft tissue sarcomas -- CUT&RUN v2

ABSTRACT: ATRX is an ATP-dependent chromatin remodeler frequently altered in sarcomas and is involved in maintaining heterochromatin and transcriptional regulation. Loss of ATRX is associated with aggressive tumor behavior, but the transcriptional regulatory mechanisms underlying ATRX-deficient sarcomas remain incompletely understood. In this study, we investigated chromatin and transcription factor regulatory changes associated with ATRX loss in sarcoma models. Our analyses identified chromatin de-repression following ATRX loss and enrichment of transcription factor motifs, including PRDM4 and NFIX. To characterize the genomic regulatory programs associated with these transcription factors, we performed CUT&RUN profiling to map transcription factor occupancy in sarcoma cells. These data provide genome-wide profiles of transcription factor binding and support investigation of the regulatory mechanisms associated with ATRX loss in sarcoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE346013 | 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.

2026-09-01 | GSE310906 | GEO

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

Project description:ATRX is an ATP-dependent chromatin remodeler frequently altered in sarcomas and plays an important role in maintaining chromatin organization and transcriptional regulation. Loss of ATRX is associated with aggressive tumor behavior, but the chromatin regulatory mechanisms underlying ATRX-deficient sarcomas remain incompletely understood. In this study, we investigated changes in chromatin accessibility associated with ATRX loss in sarcoma models. We performed ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing) to characterize genome-wide accessible chromatin landscapes in ATRX-deficient and control sarcoma cells. Our analyses identified widespread alterations in chromatin accessibility and chromatin de-repression following ATRX loss, with differential accessible regions enriched for transcription factor motifs. These ATAC-seq data provide genome-wide profiles of accessible chromatin and support investigation of ATRX-dependent regulatory elements and transcriptional programs in sarcoma.

2026-09-21 | GSE346344 | GEO

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

Project description: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.

2026-09-21 | GSE346694 | GEO

ATRX guards against aberrant differentiation in mesenchymal progenitor cells (RNA-Seq)

Project description:Alterations in the tumor suppressor ATRX are recurrently observed in several cancer types including sarcomas, which are mesenchymal neoplasms. ATRX has multiple epigenetic functions including heterochromatin formation and maintenance and regulation of transcription through modulation of chromatin accessibility. Here, we show in murine mesenchymal progenitor cells (MPCs) that Atrx deficiency aberrantly activated mesenchymal differentiation programs. This includes adipogenic pathways where ATRX loss induced expression of adipogenic transcription factors (Pparγ and Cebpα) and enhanced adipogenic differentiation in response to differentiation stimuli. These changes are linked to loss of heterochromatin near mesenchymal lineage genes together with increased chromatin accessibility and gains of active chromatin marks at putative enhancer elements and promoters. Finally, we observed depletion of H3K9me3 at transposable elements, which are derepressed including near mesenchymal genes where they could serve as regulatory elements. Our results demonstrate ATRX functions to buffer against differentiation in mesenchymal progenitor cells, which has implications for understanding ATRX loss of function in sarcomas.

2024-03-13 | GSE240027 | GEO

ATRX guards against aberrant differentiation in mesenchymal progenitor cells [RNA-seq]

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ATRX guards against aberrant differentiation in mesenchymal progenitor cells (CUT&RUN)

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ATRX guards against aberrant differentiation in mesenchymal progenitor cells [ATAC-seq]

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2024-03-13 | GSE240029 | GEO

ATRX alteration contributes to tumor growth and immune escape in pleomorphic sarcomas

Project description:Whole genome and transcriptome sequencing of a cohort of 67 leiomyosarcomas revealed ATRX to be one of the most frequently mutated genes in LMS after TP53 and RB1. While its function is well described in the ALT mechanism, we wondered whether its alteration could have complementary effects on sarcoma oncogenesis. ATRX alteration is associated with the down-expression of genes linked to differentiation in LMS, and to immunity in an additional cohort of 60 poorly differentiated sarcomas. In vitro and in vivo models showed that ATRX loss increases tumor growth rate and immune escape by decreasing the immunity load of active mast cells in sarcoma tumors. These data indicate that an alternative to unsuccessful targeting of the adaptive immune system in sarcoma could be to target the innate system. This might lead to a better outcome for sarcoma patients in terms of ATRX status.

2021-05-25 | GSE157953 | GEO

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