NSD2 Overexpression in Myeloma Enhances Dependency on Mitochondrial High Energy Phosphate Transport Facilitated by Adenylate Kinase 2 [AS_RS]

Chromosomal translocation t(4;14), a driver of NSD2 overexpression, remains a negative prognostic factor in multiple myeloma (MM). A genome-wide CRISPR screen in MM cells identified adenylate kinase 2 (AK2) as an NSD2-driven vulnerability. AK2 depletion in t(4;14) MM cells inhibited cell growth in vitro and in vivo, impaired protein folding in the ER and increased sensitivity to proteasome inhibition, consistent with a defect in shuttling ATP from the mitochondria. Moreover, AK2 suppression decreased intracellular NADP(H) critical for thioredoxin reduction, which is key for deoxyribonucleotides (dNTP) synthesis, leading to DNA replication stress and apoptosis. The increased dependence on AK2 was attributed to insufficient creatine production due to NSD2-mediated diversion of one-carbon metabolism to the epigenome and away from S-adenosylmethionine dependent creatine synthesis. Correspondingly, supplementation with creatine restored NADP(H) levels and rescued AK2-deficient cells from apoptosis. These findings revealed a novel metabolic susceptibility and promising therapeutic strategy for targeting t(4;14) MM.