EWS-WT1 Chimeric Protein in Desmoplastic Small Round Cell Tumor is a Potent Transactivator of FGFR4

Desmoplastic small round cell tumor (DSRCT) is a rare but highly aggressive malignant tumor that typically involves the abdominal or pelvic peritoneum in children and young adults [1]. This tumor is characterized histologically by solid nests of small round-cell tumor cells expressing epithelial, muscular, and neural markers, surrounded by a dense reactive stroma. This tumor is also characterized by the presence of specific EWS-WT1 fusion genes related to the recurrent chromosomal translocation, t(11;22)(p13;q12) [2,3]. EWS encodes a putative RNA binding protein of unknown function with an N-terminal domain that mediates potent transcriptional activation when fused to heterologous DNA binding domains [4]. The Wilms tumor suppressor (WT1) was initially identified based on its inactivation in Wilms tumor [5]. The chimeric proteins resulting from these chromosomal translocations usually possess gain-of-function transcriptional activities, and define histologically and biologically distinct tumor types. Alternative isoforms of either EWS-WT1(-KTS) or EWSWT1(+KTS) have also been shown to differ in DNA binding affinity and specificity [6,7]. The molecular targets and associated mechanisms of these fusion proteins have not yet been fully characterized. The molecular targets of EWS-WT1(-KTS) chimeric proteins that have been reported include insulin-like growth factor-I receptor (IGF-IR) gene [8-10]; the beta-chain of the interleukin-2/15 receptor (IL-2/15Rβ) [11]; platelet-derived growth factor-A (PDGFA) [12]; BAI1-associated protein 3 (BAIAP3), which encodes a protein implicated in regulated exocytosis; a potential regulator of growth-factor release [13]; and T-cell acute lymphoblastic leukemia-associated antigen 1 (TALLA-1) [14]. In addition, expression of the transmembrane protein, leucinerich repeat containing 15 (LRRC15), was found to be induced by EWS-WT1(+KTS) [15]. Recently, equilibrative nucleoside transporter 4 (ENT4), which encodes a pH-dependent adenosine transporter has been identified to be transcriptionally activated by both isoforms of EWS-WT1 [16]. In addition to genes involved in growth signaling that define biological behavior, it is apparent that the tumor-specific chimeric gene products also define histological characteristics [17]. However, genes that modulate histological features of DSRCT have not yet been identified as EWS-WT1 targets.