Deciphering the dynamics of histone acetylation and chromatin remodeling in multiple myeloma: a tale beyond the tails

The development of multiple myeloma is typically associated with various cytogenetic abnormalities; however, these genetic changes alone do not fully account for the observed heterogeneity in patient prognosis and treatment response. Recent studies leveraging next-generation sequencing and genomic approaches have shown that epigenetic alterations are crucial in myeloma development and therapeutic resistance. These changes contribute to high levels of transcriptomic instability and enable cellular adaptation to targeted therapies and immunotherapies through diverse evolutionary trajectories. In this regard, aberrations of histone modifications and chromatin remodeling affect various cellular processes such as DNA repair, DNA damage response, cellular survival, and apoptosis signaling, which provides a strong rationale for developing epigenetic-targeted therapies for myeloma treatment. In this review, we focus on recent advances and research gaps in understanding the deregulation of histone acetylation, a widespread and versatile process of histone modification occurring at lysine residues at the N-terminus of histone tails, and its intimate interplay with chromatin remodeling complexes in orchestrating dynamic chromatin functional states and transcriptional outputs. We also provide an updated review of epigenetic modulatory drugs targeting histone deacetylases (CREB-binding protein/p300) and bromodomain and extraterminal proteins, along with a discussion of their limitations and future perspectives in myeloma treatment.