Abstract
Fused in sarcoma: DNA damage‐inducible transcript 3 protein (FUS:DDIT3) is a chimeric fusion oncoprotein present in 90% of human myxoid liposarcomas (MLS). The study by Trautmann et al in this issue of EMBO Molecular Medicine utilizes a drop‐out RNAi screen to establish hyperactive Yes‐associated protein 1 (YAP1), a major downstream nuclear effector of the Hippo signaling pathway, as a selectively essential transcript promoting viability and growth of MLS. These observations add to a growing body of evidence underscoring the importance of dysregulation of Hippo signaling in soft‐tissue sarcomas expressing fusion oncoproteins and identify a novel target for therapeutic intervention in MLS. Comprehensive molecular characterization pipelines are needed to screen patients with advanced soft‐tissue sarcomas for the presence of druggable alterations, including but not limited to nuclear YAP1 expression in MLS, to facilitate treatment decisions and advance therapy.
Highlights
Fused in sarcoma: DNA damage-inducible transcript 3 protein (FUS:DDIT3) is a chimeric fusion oncoprotein present in 90% of human myxoid liposarcomas (MLS)
The fusion oncogene fused in sarcoma: DNA damage-inducible transcript 3 protein (FUS:DDIT3) originates from a chromosomal translocation t(12;16) (q13;p11) in 90% of human myxoid liposarcomas (MLS), belongs to the FET (FUS, EWSR1 and TAF15) family of chimeric oncoproteins, and contains the N-terminal domain of FUS juxtaposed to the DNA binding domain of the transcription factor DDIT3
FET-family and many other transcription/chromatin factor fusions are typically associated with low tumor mutational burdens, occur early in tumorigenesis to initiate and drive malignancy, and should qualify as ideal targets to selectively attack fusion-positive tumor cells. Their discovery in leukemias and sarcomas has not translated into improvements in treatment and survival rates, because they act as transcriptional dysregulators and successful pharmacological modulation using small molecules has not been possible far (Parker & Zhang, 2013)
Summary
Fused in sarcoma: DNA damage-inducible transcript 3 protein (FUS:DDIT3) is a chimeric fusion oncoprotein present in 90% of human myxoid liposarcomas (MLS). Their present study (Trautmann et al, 2019) utilized a drop-out RNAi screen in FUS:DDIT3-expressing, immortalized human mesenchymal stem cell lines as an unbiased functional genomic approach to reveal that FUS:DDIT3-expressing cells require Yesassociated protein 1 (YAP1), a downstream nuclear effector of the Hippo signaling pathway, to maintain viability and cell growth.
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