Novel mechanism ofMYCderegulation in Multiple Myeloma

Abstract

MYC deregulation occurs in 67% of multiple myeloma (MM) cases and associates with progression and worse prognosis in MM. Enhanced MYC expression is known to be driven by translocation or amplification events, but it only occurs in 40% of MM patients. Here, we describe a new mechanism of MYC regulation, whereby epigenetic regulation of MYC by increased accessibility of a cell-type specific enhancer leads to increased MYC expression. We found enhancer activity does not associate with enhancer hijacking events. We identified specific binding of c-MAF, IRF4, and SPIB transcription factors to the enhancer can activate MYC. In addition, we discovered focal amplification of this specific enhancer in approximately 4% of MM patients. Together, our findings define a new epigenetic mechanism of MYC deregulation in MM beyond known translocations or amplifications and point to the importance of non-coding regulatory elements and their associated transcription factor networks as drivers of MM progression.