RNA-Bound MYBL2 Engages the Oncogenic Transcription Factors MAFG and FRA1 to Promote Melanoma Progression

Non-mutational mechanisms, including copy number alterations and transcription factor dysregulation, are critical drivers of melanoma progression. Here, we identify the transcription factor MYBL2 as a key oncogenic driver located on frequently amplified chromosome 20q. MYBL2 overexpression promoted transformation and correlated with poor survival, yet paradoxically, the transactivation function of MYBL2 was dispensable for oncogenic activity. Instead, MYBL2 acquired a non-canonical RNA-binding function enabled by the melanoma-associated RNA landscape. Through these RNA interactions, MYBL2 reshaped the chromatin landscape toward an AP-1-permissive state and promoted chromatin association of the oncogenic transcription factors MAFG and FRA1, indirectly reprogramming tumor-promoting gene networks that predict poor outcomes across multiple cancers. Importantly, a decoy RNA that disrupts the MYBL2-RNA interaction impaired MYBL2 association with MAFG and FRA1 and suppressed melanoma cell growth. These findings establish MYBL2 as an RNA-binding-dependent, 20q gain-associated driver that promotes melanoma progression through chromatin and transcriptional network remodeling.