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

Clear cell sarcoma (CCS) is a rare soft tissue sarcoma caused by the EWS/ATF1 fusion gene. Here, we established induced pluripotent stem cells (iPSCs) from EWS/ATF1-controllable murine CCS cells harboring sarcoma-associated genetic abnormalities. Sarcoma-iPSC mice develop secondary sarcomas immediately after EWS/ATF1 induction, but only in soft tissue. EWS/ATF1 expression induces oncogene-induced senescence in most cell types in sarcoma-iPSC mice but prevents it in sarcoma cells. We identify Tppp3-expressing cells in peripheral nerves as a cell-of-origin for these sarcomas. We show cell type-specific recruitment of EWS/ATF1 to enhancer regions in CCS cells. Finally, epigenetic silencing at these enhancers induces senescence and inhibits CCS cell growth through altered EWS/ATF1 binding. Together, we propose that distinct responses to premature senescence are the basis for the cell type-specificity of cancer development. Microarray in mouse EWS/ATF1-induced sarcoma cell lines(G1297), G1297-derived iPSCs(sarcoma iPSC) and sarcoma iPSC-derived MEF(sarcoma MEF), and surgically resected human sarcoma samples (clear cell sarcoma; CCS and malignant peripheral nerve sheeth tumor; MPNST) and human clear cell sarcoma cell line with EWS/ATF1 knocked down. Total 26 samples (10 murine samples/16 human samples) were analized. In G1297 and its derivatives, we can induce EWS/ATF1 by Doxycycline-inducible expression system. We compared global gene expression change caused by EWS/ATF1 induction between G1297 and sarcoma MEF. Also, we investigated global gene expression pattern of sarcoma iPSCs and surgically resected human CCS and MPNST. A link to this sample file can be found below.