Irene Ghobrial, MD, Dana-Farber Cancer Institute, Boston, MA, discusses the identification of a novel epigenetic mechanism of MYC deregulation in patients with smoldering multiple myeloma (SMM) and newly diagnosed multiple myeloma. MYC deregulation is a key event in the progression from precursor conditions to overt multiple myeloma. Translocation and amplification of the 8q24.21 MYC locus are known to mediate MYC deregulation in some patients, but cases of MYC deregulation in patients with an intact MYC locus have also been identified. In this study, high-throughput CRISPR interference (CRISPRi) screening, chromatin immunoprecipitation sequencing and assay for transposase-accessible chromatin (ATAC)- sequencing of myeloma cells identified epigenetic alterations associated with MYC deregulation in myeloma: selective gain of chromatin accessibility at the enhancer elements and amplification of the enhancer region allow for binding of regulatory factors IRF4 and MAF. These changes can increase the transcription of MYC without known MYC chromosomal abnormalities. This interview took place at the 63rd ASH Annual Meeting and Exposition congress in Atlanta, GA.