Comparable transforming capacities and differential gene expression patterns of variant FUS/CHOP fusion transcripts derived from soft tissue liposarcomas

Abstract

The chromosomal translocation t(12;16)(q13;p11) is a common genetic alteration in myxoid and round-cell liposarcomas. It results in transcription of various chimeric FUS/CHOP fusion transcripts that encode different oncogenic proteins. Recent reports suggest that these may have different neoplastic transformation activities. To audit this hypothesis, we transfected expression plasmids for the two major variant FUS/ CHOP transcripts I and II in NIH 3T3 cells and determined the number of outgrowing foci as well as their growth potential in soft agar. In addition, we compared tumour growth in nude mice upon subcutaneous injection of the respective transfectants. No significant differences in transformation assays in vitro and in vivo were observed, suggesting that both variant transcripts confer comparable transforming activities. The histopathological picture of tumours derived from both cell populations resembles high-grade spindle cell sarcomas. This suggests that both FUS/CHOP variants cause similar patterns of differential gene expression. This hypothesis was confirmed by mRNA-expression profiles of the respective cell clones. Strong overexpression of the pentaxin-related gene (PTX), the osteoblast-specific factor 2 (osf-2), the basic Kruppel-like factor (bklf), the leucoprotease inhibitor, and the cyclophilin B were observed in both types of FUS/ CHOP-transfected cell clones. Taken together, our data suggest that different FUS/CHOP variants cause transformation of mesenchymal cells via the same pathways with comparable efficacy.

FUS-CREB3L2/L1–Positive Sarcomas Show a Specific Gene Expression Profile with Upregulation of CD24 and FOXL1

“…Our results suggest that FUS-CREB3L2 enhances the expression of CD24; however, a possible direct, or indirect, interaction between FUS-CREB3L2 and CD24 regulatory sequences remains to be proven. CD24 was upregulated in FUS-DDIT3 expressing NIH-3T3 murine fibroblasts and mesenchymal progenitor cells (37,38), perhaps suggesting the contribution of the FUS domain to the regulation of CD24. CD24 is a glycosylated cell surface mucin which is involved in T-cell proliferation, synaptic transmission, immune response, and cell adhesion through its interaction with P-selectin on endothelial cells or platelets (39,40).…”

The myxoid liposarcoma FUS-DDIT3 fusion oncoprotein deregulates NF-κB target genes by interaction with NFKBIZ

“…Deregulation of normal NF-kB functions by the FUS-DDIT3 fusion oncoprotein may affect vital functions of the normal cell and contribute to the development of MLS/ RCLS. Growth-regulating genes, such as CCND1, PTX3, JUNB and CCNE, are aberrantly or strongly expressed in FUS-DDIT3-expressing cells (Olofsson et al, 2004;Schwarzbach et al, 2004), and these genes have been shown to be regulated by NF-kB factors (Biegel et al, 1993;Diffin et al, 1994;Basile et al, 1997;Hinz et al, 1999). Interaction between FUS-DDIT3 and NFKBIZ may thus lead to transcriptional deregulation of these and many other NF-kB-controlled target genes.…”

High-Resolution Genomic Profiling Reveals Association of Chromosomal Aberrations on 1q and 16p with Histologic and Genetic Subgroups of Invasive Breast Cancer

“…BCL7C was identified by its similarity to BCL7A, which has been shown to be part of a three-way gene translocation in a Burkitt lymphoma cell line (40). The RNA-binding protein FUS was shown to participate in a fusion protein playing an important role in malignant liposarcomas (41). Further studies will be needed to elucidate their role in lobular breast cancer with 16p gain in general.…”