Cell-type dependent enhancer binding of the EWS/ATF1 fusion gene in clear cell sarcomas

Komura, Shingo; Ito, Kenji; Ohta, Sho; Ukai, Tomoyo; Kabata, Mio; Itakura, Fumiaki; Semi, Katsunori; Matsuda, Yutaka; Hashimoto, K; Shibata, Hirofumi; Sone, Masamitsu; Jo, Norihide; Sekiguchi, Kenichi; Ohno, Takatoshi; Akiyama, Haruhiko; Shimizu, Katsuji; Woltjen, Knut; Ozawa, Manabu; Toguchida, Junya; Yamamoto, Takuya; Yamada, Yoshihiko

doi:10.1038/s41467-019-11745-1

Cited by 24 publications

(26 citation statements)

References 51 publications

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“…In one model, tumors arise only when the fusion is expressed in a mesenchymal compartment [ 34 ]. In the second, however, tumors arise only in neural crest-derived peripheral nerve cells, while expression in other tissues induces senescence [ 35 ]. Thus, developing human models in different cellular contexts and differentiation stages becomes critical for resolving the issues.…”

Section: Discussionmentioning

confidence: 99%

Generation of human embryonic stem cell models to exploit the EWSR1-CREB fusion promiscuity as a common pathway of transformation in human tumors

et al. 2021

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Chromosomal translocations constitute driver mutations in solid tumors and leukemias. The mechanisms of how related or even identical gene fusions drive the pathogenesis of various tumor types remain elusive. One remarkable example is the presence of EWSR1 fusions with CREB1 and ATF1, members of the CREB family of transcription factors, in a variety of sarcomas, carcinomas and mesotheliomas. To address this, we have developed in vitro models of oncogenic fusions, in particular, EWSR1-CREB1 and EWSR1-ATF1, in human embryonic stem (hES) cells, which are capable of multipotent differentiation, using CRISPR-Cas9 technology and HDR together with conditional fusion gene expression that allows investigation into the early steps of cellular transformation. We show that expression of EWSR1-CREB1/ATF1 fusion in hES cells recapitulates the core gene signatures, respectively, of angiomatoid fibrous histiocytoma (AFH) and gastrointestinal clear cell sarcoma (GI-CCS), although both fusions lead to cell lethality. Conversely, expression of the fusions in hES cells differentiated to mesenchymal progenitors is compatible with prolonged viability while maintaining the core gene signatures. Moreover, in the context of a mesenchymal lineage, the proliferation of cells expressing the EWSR1-CREB1 fusion is further extended by deletion of the tumor suppressor TP53 . We expect the generation of isogenic lines carrying oncogenic fusions in various cell lineages to expand our general understanding of how those single genetic events drive tumorigenesis while providing valuable resources for drug discovery.

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Section: Discussionmentioning

confidence: 99%

Generation of human embryonic stem cell models to exploit the EWSR1-CREB fusion promiscuity as a common pathway of transformation in human tumors

et al. 2021

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“…EWSR1 and FUS are multifunctional proteins that belong to the FET family of RNA-binding proteins. The EWSR/ATF fusion gene product, which consists of the N-terminal transactivation domain of EWSR1 and the C-terminal DNA binding domain of ATF1, has enhanced transcriptional activity and functions as a key driver oncogene (50,51). Thus, these fusion gene products may be involved in the resistance to chemotherapy in sarcomas.…”

Section: Discussionmentioning

confidence: 99%

BRCA1/ATF1-Mediated Transactivation is Involved in Resistance to PARP Inhibitors and Cisplatin

Endo

Yoshino

Shirota

et al. 2021

Cancer Research Communications

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Homologous recombination (HR)-deficient cells are sensitive to PARP inhibitors through a synthetic lethal effect. We previously developed an HR activity assay named Assay of Site-Specific HR Activity (ASHRA). Here, we evaluated the HR activity of 30 missense variants of BRCA1 by ASHRA and found that several BRCA1 variants showed intermediate HR activity, which was not clearly discerned by our previous analyses using a conventional method. HR activity measured by ASHRA was significantly correlated with sensitivity to olaparib. However, cells expressing the severely HR-deficient BRCA1-C61G variant were resistant to olaparib, and resistance was dependent on high expression of activating transcription factor 1 (ATF1), which binds to BRCA1 and activates the transcription of target genes to regulate cell proliferation. The BRCA1-C61G variant bound to ATF1 and stimulated ATF1-mediated transactivation similar to wild-type BRCA1. High expression of ATF1 conferred resistance to olaparib and cisplatin activating BRCA1/ATF1-mediated transcription without affecting HR activity in BRCA2-knockdown or RAD51-knockdown cells, but not in BRCA1-knockdown cells. These results suggest that ASHRA is a useful method to evaluate HR activity in cells and to predict the sensitivity to PARP inhibitors. The expression level of ATF1 might be an important biomarker of the effect of PARP inhibitors and platinum agents on HR-deficient tumors with the BRCA1-C61G variant or alteration of non-BRCA1 HR factors such as BRCA2 and RAD51. Significance: ASHRA could evaluate HR activity in cells and predict the sensitivity to PARP inhibitors. High expression level of ATF1 may predict the resistance of BRCAness tumors with alterations of non-BRCA1 HR factors to PARP inhibitors and platinum agents.

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“…Although CCS may display additional genomic aberrations, t(12;22)(q13;q12) is the only genetic alteration found in more than 90% of cases, and the resulting EWSR1-ATF1 fusion gene is believed to represent the major driver of this disease ( https://mitelmandatabase.isb-cgc.org ). EWSR1-ATF1 expression alone is sufficient to induce CCS-like tumors in mice, and stem cells derived from the mesenchymal or neural crest lineages have been proposed to be particularly permissive for EWSR1-ATF1 dependent transformation 8 – 10 .…”

Section: Introductionmentioning

confidence: 99%

EWSR1-ATF1 dependent 3D connectivity regulates oncogenic and differentiation programs in Clear Cell Sarcoma

et al. 2022

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Oncogenic fusion proteins generated by chromosomal translocations play major roles in cancer. Among them, fusions between EWSR1 and transcription factors generate oncogenes with powerful chromatin regulatory activities, capable of establishing complex gene expression programs in permissive precursor cells. Here we define the epigenetic and 3D connectivity landscape of Clear Cell Sarcoma, an aggressive cancer driven by the EWSR1-ATF1 fusion gene. We find that EWSR1-ATF1 displays a distinct DNA binding pattern that requires the EWSR1 domain and promotes ATF1 retargeting to new distal sites, leading to chromatin activation and the establishment of a 3D network that controls oncogenic and differentiation signatures observed in primary CCS tumors. Conversely, EWSR1-ATF1 depletion results in a marked reconfiguration of 3D connectivity, including the emergence of regulatory circuits that promote neural crest-related developmental programs. Taken together, our study elucidates the epigenetic mechanisms utilized by EWSR1-ATF1 to establish regulatory networks in CCS, and points to precursor cells in the neural crest lineage as candidate cells of origin for these tumors.

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Cell-type dependent enhancer binding of the EWS/ATF1 fusion gene in clear cell sarcomas

Cited by 24 publications

References 51 publications

Generation of human embryonic stem cell models to exploit the EWSR1-CREB fusion promiscuity as a common pathway of transformation in human tumors

Generation of human embryonic stem cell models to exploit the EWSR1-CREB fusion promiscuity as a common pathway of transformation in human tumors

BRCA1/ATF1-Mediated Transactivation is Involved in Resistance to PARP Inhibitors and Cisplatin

EWSR1-ATF1 dependent 3D connectivity regulates oncogenic and differentiation programs in Clear Cell Sarcoma

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