Super enhancer-mediated upregulation of HJURP promotes growth and survival of t(4;14)-positive multiple myeloma.

Multiple myeloma (MM) is an incurable malignancy with marked clinical and genetic heterogeneity. The cytogenetic abnormality t(4;14) (p16.3;q32.3) confers aggressive behavior in MM. Recently, essential oncogenic drivers in a wide range of cancers have been shown to be controlled by super-enhancers (SE). We used ChIP-seq of the active enhancer marker H3K27ac to profile unique SEs in t(4;14)-translocated MM. The histone chaperone HJURP was aberrantly overexpressed in t(4;14)-positive MM due to transcriptional activation by a distal SE induced by the histone lysine methyltransferase NSD2. Silencing of HJURP with shRNA or CRISPR interference of SE function impaired cell viability and led to apoptosis. Conversely, HJURP overexpression promoted cell proliferation and abrogated apoptosis. Mechanistically, the NSD2/BRD4 complex positively co-regulated HJURP transcription by binding the promoter and active elements of its SE. In summary, this study introduces SE profiling as an efficient approach to identify new targets and understand molecular pathogenesis in specific subtypes of cancer. Moreover, HJURP could be a valuable therapeutic target in t(4;14)-positive myeloma patients.