Multiple myeloma (MM) is an incurable malignancy of plasma cells, characterized by marked clinical and genetic heterogeneity. The t(4;14) chromosomal translocation confers aggressive behaviour in MM with poor survival rate. This t(4;14) cytogenetic abnormality results into over-expression of NSD2 gene, a histone lysine methyltransferase.Super-enhancers are regarded as a large trunk of DNA fragments that activate transcription in a “super” strong fashion. These specific DNA regions work together other co-activators and transcription factors to propel cancer-promoting gene.

In a recent study published in Cancer Research, a team led by Prof Chng Wee-Joo, in collaboration with A/Prof Takaomi Sanda at the Cancer Science Institute of Singapore (CSI Singapore) has performed comprehensive profiling of epigenetic markers for this group of patients. They uncovered and characterized a specific area of DNA with high super-enhancer activity at chromosome 2 near HJURP gene, which plays an important role in precise separation of replicated chromosomes during cell cycle. Findings revealed that this super-enhancer region was activated by NSD2 gene, which is a hallmark of t(4;14)-MM. In addition, BRD4, a well characterized transcriptional and epigenetic regulator, was also recruited to these sites and help increase transcription of HJURP gene messages.

Overall, the activation of this SE region stimulates HJURP overexpression, in turn, promoting uncontrolled cell proliferation and blocking cell death. The team then experimentally treated the myeloma cells using two different approaches, ie, by short hairpin RNA (shRNA) knocking down HJURP genes or dcas9-CRISPR inhibition of super-enhancer function. Both approaches decreased cell viability and led to cell apoptosis in t(4;14) positive cells, but not in t(4;14) negative cells.

This study demonstrates that super enhancer profiling is an efficient platform to uncover novel targets in MM and other types of cancer as well, underscoring the therapeutic potential of HJURP as a valuable target for fighting t(4;14)-positive myeloma. The team is currently developing strategies to translate these findings into clinical practice, which will in turn contribute to the development of novel and therapeutic modality for such patients.

Read more about the study here.