GSE208739
PKCa RNA-seq in t(4;14) cells
Multiple myeloma (MM) cells undergo metabolic reprogramming in response to a hypoxic and nutrient-deprived bone marrow microenvironment. However, it is unclear whether primary oncogenes in recurrent translocations drive metabolic heterogeneity that can present new vulnerabilities for therapeutic targeting. t(4;14) translocation leads to the universal overexpression of histone methyltransferase MMSET II that promotes plasma cell transformation through a global increase in H3K36me2. We identified PKCa as a novel epigenetic target that contributes to the oncogenic potential of MMSET II. RNA-sequencing of t(4;14) cell lines revealed a significant enrichment in the regulation of metabolic processes by PKCa, and the glycolytic gene, hexokinase 2 (HK2), is transcriptionally regulated by PKCa in a PI3K/Akt-dependent manner. Loss of PKCa displaces mitochondria-bound HK2 and reversed sensitivity towards the glycolytic blocker 3-Bromopyruvate. Additionally, we observed a metabolic shift to a less energetic state through the reduction in oxidative and glycolytic fluxes, resulting in an overall decrease in ATP production. We employed metabolomics and lactate emerged as a differential metabolite associated with PKCa. This conferred PKCa with immunomodulatory drug (IMiDs) resistance in a cereblon-independent manner and could be phenocopied by either overexpression of HK2 or direct supplementation of lactate. Altogether, we revealed novel insights into the epigenetic and metabolism crosstalk in MM and the opportunity for therapeutic intervention that leverages on the distinct metabolic program in t(4;14) myeloma. Overall design: t(4;14) cell lines KMS18 and KMS28BM with stable knockdown of PKCa