The BRAF Pseudogene Shows Oncogenic Potential in Human B-Cell Lymphoma

Pseudogenes are a subclass of long noncoding RNA genes that posttranscriptionally regulate the expression of their protein-coding parental genes and promote cell transformation in vitro; however, in vivo evidence for their oncogenic potential is lacking. The BRAF pseudogene, BRAFP1, is overexpressed in a variety of cancers, prompting Karreth and colleagues to assess its oncogenic role in vivo. Ectopic expression of human BRAFP1 or its murine ortholog, Braf-rs1, elevated BRAF protein and MAPK activity and increased proliferation in cancer cell lines in a DICER1-dependent manner, suggesting that the effect of the BRAF pseudogene is mediated via regulation of miRNAs. Indeed, the ability of BRAFP1 to regulate BRAF expression was repressed by miRNAs shared by BRAF and BRAFP1 or by mutation of miRNA response elements in the BRAFP1 3′ untranslated region (3'UTR), indicating that BRAFP1 regulates BRAF via competitive endogenous RNA (ceRNA)–mediated miRNA sequestration. Interestingly, transgenic mice engineered to express Braf-rs1 developed splenomegaly, enlarged lymph nodes, and large tumor nodules that were histologically consistent with human diffuse large B-cell lymphoma (DLBCL). These tumors were transplantable and dependent on continuous Braf-rs1 expression and MAPK signaling for tumor maintenance. In addition, Braf-rs1 variants harboring either the coding sequence or 3'UTR fragments also displayed an oncogenic phenotype in vivo, further supporting the notion that the BRAF pseudogene functions as a ceRNA. Importantly, BRAFP1 was not expressed in primary B cells but was expressed in 30% of primary DLBCL and 20% of DLBCL cell lines, as well as in various other cancer cell lines, and exhibited genomic aberrations in numerous cancer types. Furthermore, overexpression of BRAFP1 increased BRAF levels, MAPK activity, and DLBCL cell proliferation, whereas depletion of endogenous BRAFP1 elicited the opposite effect. Taken together, these findings suggest a causal role for the BRAF pseudogene in DLBCL and other human cancers.

Karreth FA, Reschke M, Ruocco A, Ng C, Chapuy B, Léopold V, et al. The BRAF pseudogene functions as a competitive endogenous RNA and induces lymphoma in vivo. Cell 2015;161:319–32.