These results establish that the unique oncogene duet of coexisting BRAF V600E and TERT promoter mutations is a fundamental genetic background that cooperatively drives progression and aggressiveness of some human cancers. However, the molecular mechanism underpinning the synergistic oncogenic operations of the two oncogenes is undefined. Specifically, a fundamental question as to how BRAF V600E and mutant TERT, which each apparently represents a different molecular system, are functionally bridged at the molecular level in cooperatively promoting human cancer aggressiveness remains to be answered. We mechanistically explored this issue in the present study by testing our hypothesis that the BRAF V600E-activated MAPK pathway may selectively upregulate the mutant TERT through a molecular mechanism that mediates the activation of the mutant TERT promoter-selective transcriptional machinery, thus functionally connecting the two oncogenes in cooperatively promoting oncogenesis. We identify FOS as playing such a critical role in this important mechanism of human oncogenesis. Specifically, we identify a molecular mechanism for the activation of mutant TERT by the BRAF V600E/MAP kinase pathway, in which FOS as a transcriptional factor of the GABPB promoter promotes the expression of GABPB; the latter complexes with GABPA and selectively binds and activates the mutant TERT promoter, robustly upregulating the expression of TERT, thus functionally bridging the two oncogenes in cooperatively promoting oncogenesis.