MAF converts metabolic state into superenhancer architecture and dependency in myeloma [RPMI8226 ChIP-Seq]

By integrating metabolomic, epigenomic and chromatin architecture analyses, we identify a previously unrecognized role for MAF in metabolically driven histone acetylation, including the superenhancer-defining mark H3K27ac, through enhanced acetyl-CoA availability derived from rewired glutamine anaplerosis.

The channeling of acetylation donors to high-demand enhancer microdomains is facilitated by nucleus-localizing metabolic enzyme citrate synthase, thereby alleviating metabolically constrained chromatin states. This process is further reinforced by MAF-dependent transcriptional regulation of the rate-limiting acetyltransferase p300, culminating in a globally elevated yet spatially precise hyperacetylated chromatin landscape that drives expression of core myeloma oncogenes.