ATF4:p52 Complex Activates Oncogenic Enhancers in Multiple Myeloma via p300/CBP Recruitment to Regulate BACH1

Multiple myeloma (MM) is a B-cell malignancy accounting for 20% of all blood-associated cancers. MM patients with a poorer prognosis and high-risk stratification were previously observed to be causally linked to the constitutive activation of non-canonical NF-kB (ncNF-kB) pathway. Consistent with this, the ncNF-kB p52 transcription factor was earlier found to regulate the enhancer landscape of MM to potentiate oncogenic transcription. However, the mechanism by which aberrant p52 expression is involved in coordinating enhancer activity has not been well explored. In this study, we analysed H3K27ac ChIP-seq and ATAC-seq data from MM cell lines and patient samples to screen for putative transcription factors that cooperate with p52 to regulate enhancers activated in MM. We report that ATF4 interacts with p52 and together, this complex mediates the activity of a subset of MM-associated enhancers through the recruitment of histone acetyltransferases (HATs), p300 and CBP (CREB-binding protein). We also identified a novel ATF4:p52 regulated target gene BACH1 under the regulation of a proximal super-enhancer, which was found to drive oncogenesis in MM by promoting cell cycle progression and proliferation. Together, our findings provide further mechanistic insights into how aberrant enhancer activation observed in MM tumours could lead to disease progression.