Atrx deletion impairs CGAS/STING signaling and increases sarcoma response to radiation and oncolytic herpesvirus

Floyd, Robert W.; Pierpoint, Matthew; Su, Chang; Patel, Rekha C.; Luo, Lixia; Deland, Katherine; Wisdom, Amy J.; Zhu, Daniel; Ma, Yan; DeWitt, Suzanne Bartholf; Williams, Nerissa; Lazarides, Alexander L.; Somarelli, Jason A.; Corcoran, David L.; Eward, William C.; Cardona, Diana M.; Kirsch, David G.

doi:10.1172/jci149310

Cited by 10 publications

(13 citation statements)

References 65 publications

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“…We observed similar changes in histone modifications and chromatin accessibility in a patient-derived UPS cell in which we knocked out ATRX. At the transcriptional level, ATRX deficient UPS cells upregulated TEs, including ERVs, a finding we also observed in a re-analysis of datasets from a mouse model of ATRX deficient UPS ( 91 ). In addition, epigenetic changes in ATRX deficient UPS led us to uncover a selective sensitivity of ATRX deficient UPS cell to Wnt pathway inhibition by tegavivint.…”

Section: Discussionsupporting

confidence: 71%

“…Gene set enrichment analysis highlighted pathways involved in cell cycle regulation and mitosis among upregulated genes and in genes involved in immune response among downregulated genes ( Supplementary Figure S12C , Supplementary Table S35 ). Notably, similar pathways were downregulated in an ATRX deficient (versus Atrx WT) mouse model of UPS ( 91 ) suggesting that while ATRX has an important role in regulating transcription in both MPC and UPS, the specific consequences of ATRX deficiency may depend on context, potentially including concurrent p53 loss of function, an event shared in both the human cell lines ( 29 ) and mouse UPS ( 91 ).…”

Section: Resultsmentioning

confidence: 99%

“…These results were similar observations in MPCs (Figure 3E – G ). To additionally validate the association of ATRX loss and TE de-repression in the UPS context, we analyzed RNA-seq data from a study reporting a mouse model of ATRX deficient versus retained UPS ( 91 ). TEs were upregulated in the Atrx KO tumors, with the ERV superfamily, including ERV1, ERVL and ERVK, predominating ( Supplementary Figure S12D , Supplementary Table S37 ).…”

Section: Resultsmentioning

confidence: 99%

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ATRX guards against aberrant differentiation in mesenchymal progenitor cells

Fang,

Barrows,

Dabas

et al. 2024

Nucleic Acids Research

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Alterations in the tumor suppressor ATRX are recurrently observed in 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 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. We additionally observed depletion of H3K9me3 at transposable elements, which are derepressed including near mesenchymal genes where they could serve as regulatory elements. Finally, we demonstrated that loss of ATRX in a mesenchymal malignancy, undifferentiated pleomorphic sarcoma, results in similar epigenetic disruption and de-repression of transposable elements. Together, our results reveal a role for ATRX in maintaining epigenetic states and transcriptional repression in mesenchymal progenitors and tumor cells and in preventing aberrant differentiation in the progenitor context.

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Section: Discussionsupporting

confidence: 71%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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ATRX guards against aberrant differentiation in mesenchymal progenitor cells

Fang,

Barrows,

Dabas

et al. 2024

Nucleic Acids Research

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“…In osteosarcoma, mutations in ATRX lead to upregulation of NF- κ B, extracellular matrix remodeling, increased B3 integrin expression, and more aggressive tumor cell phenotypes, including increased growth, migration, invasion, and metastasis [ 5 ]. In STS, ATRX loss is associated with increased chromosomal and mitotic instability, as well as a reduction in disease-specific survival [ 21 ]. ATRX mutation was also associated with targetable therapeutic vulnerabilities in STS, including increased sensitivity to radiation therapy and oncolytic herpesvirus [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

“…In STS, ATRX loss is associated with increased chromosomal and mitotic instability, as well as a reduction in disease-specific survival [ 21 ]. ATRX mutation was also associated with targetable therapeutic vulnerabilities in STS, including increased sensitivity to radiation therapy and oncolytic herpesvirus [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

ATRX and Its Prognostic Significance in Soft Tissue Sarcoma

Cullen,

Floyd,

Dow

et al. 2024

Sarcoma

Self Cite

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Purpose. Recently, the association between ATRX and a more aggressive sarcoma phenotype has been shown. We performed a retrospective study of sarcomas from an individual institution to evaluate ATRX as a prognosticator in soft tissue sarcoma. Experimental Design. 128 sarcomas were collected from a single institution and stained for ATRX. The prognostic significance of these markers was evaluated in a smaller cohort of primary soft tissue sarcomas (n = 68). Kaplan–Meier curves were created for univariate analysis, and Cox regression was utilized for multivariate analysis. Results. High expression of ATRX was found to be a positive prognostic indicator for overall survival and metastasis-free survival in our group of soft tissue sarcomas both in univariate analysis and multivariate analysis (HR: 0.38 (0.17–0.85), P=0.02 and HR: 0.49 (0.24–0.99), P=0.05, respectively). Conclusions. High expression of ATRX is a positive prognostic indicator of overall survival and metastasis-free survival in patients with STS. This is consistent with studies in osteosarcoma, which indicate possible mechanisms through which loss of ATRX leads to more aggressive phenotypes. Future prospective clinical studies are required to validate the prognostic significance of these findings.

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