In a recently published study, researchers revealed that NSD2 overexpression in t(4;14) multiple myeloma (MM) redirects S-adenosylmethionine (SAM) toward excessive methylation of the epigenome, specifically histone H3K36 dimethylation. This diversion impairs creatine biosynthesis, creating a reliance on adenylate kinase 2 (AK2) for mitochondrial adenosine triphosphate distribution. The study highlights how NSD2’s overactivity depletes cellular one-carbon metabolism, shifting resources away from critical biosynthetic pathways, like creatine production, and increasing dependency on AK2 for maintaining cellular energy balance.

The findings are notable for identifying a potential therapeutic target in AK2 for treating t(4;14) MM, where direct targeting of NSD2 has been challenging. This discovery suggests a therapeutic window for AK2 inhibition, especially given the slow progress in targeting NSD2 itself. Additionally, AK2 dependency appears relevant to other lymphoid malignancies, broadening the implications of this research. With ongoing clinical trials exploring inhibitors of NSD2’s methyltransferase activity and preclinical work on targeting NSD2’s PWWP1 domain, the study paves the way for novel therapeutic strategies in MM and potentially other hematologic cancers.

Reference: Bergsagel PL, Chesi M. UnSETtling energy dependence of t(4;14) MM. Blood. 2024;144(3):244-245. doi: 10.1182/blood.2024024871.