NSD2 drives t(4;14) myeloma cell dependence on adenylate kinase 2 by diverting one-carbon metabolism to the epigenome

Chromosomal translocation (4;14), an adverse prognostic factor in multiple myeloma (MM), drives overexpression of the histone methyltransferase NSD2. A genome-wide CRISPR screen in MM cells identified adenylate kinase 2 (AK2), an enzyme critical for high energy phosphate transfer from the mitochondria, as an NSD2-driven vulnerability. AK2 suppression in t(4;14) MM cells decreased NADP(H) critical for conversion of ribonucleotides to deoxyribonucleosides, leading to replication stress, DNA …