‘Junk’ RNA produces lymphoma phenotype
Mice overexpressing the BRAF pseudogene displayed higher levels of the BRAF protein and hyperactivation of the MAPK pathway, which suggests this axis is critical to cancer development.
The researchers confirmed this by inhibiting the MAPK pathway with GSK1120212, a MEK inhibitor that dramatically reduced the cancer cells’ ability to infiltrate the liver in transplantation experiments.
The investigators further validated the microRNA decoy function of the BRAF pseudogene by creating two additional transgenic mice, one overexpressing the front half of the BRAF pseudogene, and the other overexpressing the back half.
Both of these mouse models developed the same lymphoma phenotype as the mice overexpressing the full-length pseudogene, a result the researchers described as “astonishing.”
“We never expected that portions of the BRAF pseudogene could elicit a phenotype,” Dr Karreth said. “[W]hen both front and back halves induced lymphomas, we were certain the BRAF pseudogene was functioning as a microRNA decoy.”
The investigators also found the BRAF pseudogene is overexpressed in human B-cell lymphomas, and the genomic region containing the BRAF pseudogene is commonly amplified in a variety of human cancers. This suggests the group’s murine findings are of relevance to human cancer development.
Moreover, the researchers found that silencing the BRAF pseudogene in human cancer cell lines that expressed higher levels led to reduced cell proliferation. This reinforces the importance of the pseudogene and suggests a therapy that reduces BRAF pseudogene levels may be beneficial to certain cancer patients.
“While we have been busy focusing on the genome’s 20,000 coding genes, we have neglected perhaps as many as 100,000 noncoding genetic units,” Dr Pandolfi noted. “Our new findings not only tell us that we need to characterize the role of all of these non-coding pseudogenes in cancer, but, more urgently, suggest that we need to increase our understanding of the non-coding ‘junk’ of the genome and incorporate this information into our personalized medicine assays.”
“The game has to start now. We have to sequence and analyze the genome and the RNA transcripts from the non-coding space.” 
