NSD2 drives t(4;14) myeloma cell dependence on adenylate kinase 2 by diverting one-carbon metabolism to the epigenome.
Amin SobhElena EncinasAlisha M PatelGreeshma SurapaneniEmilie BonillaCharlotte Leonie KaestnerJanai PoullardMonica ClerioKarthik VasanTzipporah FreemanDong-Wen LvDaphné Dupéré-RicherAlberto RivaBenjamin G BarwickDaohong ZhouLawrence H BoiseConstantine S MitsiadesBaek KimRichard L BennettNavdeep S ChandelJonathan D LichtPublished in: Blood (2024)
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 damage and apoptosis. Driving a large genome-wide increase in chromatin methylation, NSD2 overexpression depletes S-adenosylmethionine (SAM), compromising synthesis of creatine from its precursor guanidinoacetate. Creatine supplementation restored NADP(H) levels, reduced DNA damage and rescued AK2-deficient t(4;14) MM cells. As the creatine phosphate shuttle constitutes an alternative means for mitochondrial high energy phosphate transport, these results indicate that NSD2-driven creatine depletion underlies the hypersensitivity of t(4;14) MM cells to AK2 loss. Furthermore, AK2 depletion in t(4;14) cells impaired protein folding in the endoplasmic reticulum consistent with impaired utilization of mitochondrial ATP. Accordingly, AK2 suppression increased sensitivity of MM cells to proteasome inhibition. These findings delineate a novel mechanism in which aberrant transfer of carbon to the epigenome creates a metabolic vulnerability, with direct therapeutic implications for t(4;14) MM.
Keyphrases
- cell cycle arrest
- induced apoptosis
- genome wide
- dna damage
- dna methylation
- oxidative stress
- cell death
- endoplasmic reticulum stress
- multiple myeloma
- transcription factor
- gene expression
- prognostic factors
- endoplasmic reticulum
- dna repair
- emergency department
- signaling pathway
- mesenchymal stem cells
- copy number
- single cell
- single molecule
- high throughput
- molecular dynamics simulations
- tyrosine kinase
- reactive oxygen species
- bone marrow
- adverse drug
- drug induced
- wild type