Bcr‐Abl regulation of sphingomyelin synthase 1 reveals a novel oncogenic‐driven mechanism of protein up‐regulation

Bcr‐Abl (break‐point cluster region‐abelson), the oncogenic trigger of chronic myelogenous leukemia (CML), has previously been shown to up‐regulate the expression and activity of sphingomyelin synthase 1 (SMS1), which contributes to the proliferation of CML cells; however, the mechanism by which this increased expression of SMS1 is mediated remains unknown. In the current study, we show that Bcr‐Abl enhances the expression of SMS1 via a 30‐fold up‐regulation of its transcription. Of most interest, the Bcr‐Abl‐regulated transcription of SMS1 is initiated from a novel transcription start site (TSS) that is just upstream of the open reading frame. This shift in TSS utilization generates an SMS1 mRNA with a substantially shorter 5′ UTR compared with its canonical mRNA. This shorter 5′ UTR imparts a 20‐fold greater translational efficiency to SMS1 mRNA, which further contributes to the increase of its expression in CML cells. Therefore, our study demonstrates that Bcr‐Abl increases SMS1 protein levels via 2 concerted mechanisms: up‐regulation of transcription and enhanced translation as a result of the shift in TSS utilization. Remarkably, this is the first time that an oncogene—Bcr‐Abl—has been demonstrated to drive such a mechanism that up‐regulates the expression of a functionally important target gene, SMS1 .—Moorthi, S., Burns, T. A., Yu, G.‐Q., Luberto, C. Bcr‐Abl regulation of sphingomyelin synthase 1 reveals a novel oncogenic‐driven mechanism of protein up‐regulation. FASEB J . 32, 4270–4283 (2018). www.fasebj.org