Selective Enhancer Gain of Function Deregulates MYC Expression in Multiple Myeloma.
Mahshid RahmatM Kendell ClementJean-Baptiste AlbergeRomanos Sklavenitis-PistofidisRohan KodguleCharles P FulcoDaniel Heilpern-MalloryKatarina NilssonDavid M DorfmanJesse M EngreitzGad A GetzLuca PinelloRussell J H RyanIrene M GhobrialPublished in: Cancer research (2024)
MYC deregulation occurs in the majority of multiple myeloma (MM) cases and is associated with progression and worse prognosis. Enhanced MYC expression occurs in about 70% of MM patients, but it is known to be driven by translocation or amplification events in only ~40% of myelomas. Here, we used CRISPR interference (CRISPRi) to uncover an epigenetic mechanism of MYC regulation whereby increased accessibility of a plasma cell-type specific enhancer leads to increased MYC expression. This native enhancer activity was not associated with enhancer hijacking events but led to specific binding of c-MAF, IRF4, and SPIB transcription factors that activated MYC expression in the absence of known genetic aberrations. In addition, focal amplification was another mechanism of activation of this enhancer in approximately 3.4% of MM patients. Together, these findings define an 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.
Keyphrases
- transcription factor
- dna binding
- binding protein
- poor prognosis
- end stage renal disease
- multiple myeloma
- ejection fraction
- chronic kidney disease
- newly diagnosed
- gene expression
- dna methylation
- peritoneal dialysis
- prognostic factors
- genome wide identification
- genome wide
- crispr cas
- patient reported outcomes
- long non coding rna
- dendritic cells
- immune response