Oncogenic properties via MAPK signaling of the SOX5-RAF1 fusion gene identified in a wild-type NRAS/BRAF giant congenital nevus.

ABSTRACT

We recently reported an RAF rearrangement without NRAS or BRAF mutations in lesions from Giant Congenital Melanocytic Nevi (CMN). The new gene fusion involves the 5'-end of the promoter-containing N terminus of the SOX5 gene fused to exons 7-16 of the 3'-end of RAF1 gene leading to a SOX5-RAF1 fusion transcript which loses the auto-inhibitory CR1 domain but retains the complete in-frame coding sequence for the C-Terminal kinase domain of the RAF1. Stable expression of SOX5-RAF1 fusion induced growth factor-independent cell growth in murine hematopoietic Ba/F3 cells and melan-a immortalized melanocytes. Besides, it led to the transformation of both Ba/F3 and NIH 3T3 cells as revealed by colony formation assays. Furthermore, its expression results in MAPK activation assessed by increased levels of p-ERK protein in the cytosol of transduced cells. Treatment with Sorafenib and UO126 inhibited proliferation of Ba/F3-SOX5-RAF1 cells in the absence of IL3 but not the PLX 4720, a specific inhibitor of BRAF. Moreover, the tumorigenic and metastatic capacities of SOX5-RAF1 were assessed in vivo. These results indicate that SOX5-RAF1, a driver event for CMN development, has oncogenic capacity. Thus, sequencing of CMN transcriptomes may lead to the identification of this druggable fusion and interfere with the progression toward melanoma.