The BRAF Pseudogene Functions as a Competitive Endogenous RNA and Induces Lymphoma In Vivo

• Published in: Cell 2015-04, Vol.161 (2), p.319-332
• Main Authors: Karreth, Florian A., Reschke, Markus, Ruocco, Anna, Ng, Christopher, Chapuy, Bjoern, Léopold, Valentine, Sjoberg, Marcela, Keane, Thomas M., Verma, Akanksha, Ala, Ugo, Tay, Yvonne, Wu, David, Seitzer, Nina, Velasco-Herrera, Martin Del Castillo, Bothmer, Anne, Fung, Jacqueline, Langellotto, Fernanda, Rodig, Scott J., Elemento, Olivier, Shipp, Margaret A., Adams, David J., Chiarle, Roberto, Pandolfi, Pier Paolo
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; Humans; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphoma, Large B-Cell, Diffuse - metabolism; Mice; Molecular Sequence Data; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins B-raf - metabolism; Pseudogenes; RNA - metabolism
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2015.02.043

Research over the past decade has suggested important roles for pseudogenes in physiology and disease. In vitro experiments demonstrated that pseudogenes contribute to cell transformation through several mechanisms. However, in vivo evidence for a causal role of pseudogenes in cancer development is lacking. Here, we report that mice engineered to overexpress either the full-length murine B-Raf pseudogene Braf-rs1 or its pseudo “CDS” or “3′ UTR” develop an aggressive malignancy resembling human diffuse large B cell lymphoma. We show that Braf-rs1 and its human ortholog, BRAFP1, elicit their oncogenic activity, at least in part, as competitive endogenous RNAs (ceRNAs) that elevate BRAF expression and MAPK activation in vitro and in vivo. Notably, we find that transcriptional or genomic aberrations of BRAFP1 occur frequently in multiple human cancers, including B cell lymphomas. Our engineered mouse models demonstrate the oncogenic potential of pseudogenes and indicate that ceRNA-mediated microRNA sequestration may contribute to the development of cancer. [Display omitted] •The BRAF pseudogene functions as a ceRNA for BRAF in humans and mice•Braf-rs1 overexpression promotes B cell lymphoma in mice•Silencing of BRAFP1 affects MAPK signaling and proliferation of human cancer cells•Genomic gains and aberrant expression of BRAFP1 are found in various human cancers The in vivo evidence for the regulatory activity of pseudogenes has been lacking, and their role in disease progression has been correlative. This study now shows that transgenic expression of the BRAF pseudogene induces a malignancy in mice resembling human diffuse large B cell lymphoma, establishing its oncogenic function.