TY - JOUR T1 - IL-32 is a metabolic regulator promoting survival and proliferation of malignant plasma cells JF - bioRxiv DO - 10.1101/2021.02.22.431638 SP - 2021.02.22.431638 AU - Kristin Roseth Aass AU - Robin Mjelle AU - Martin H. Kastnes AU - Synne S. Tryggestad AU - Luca M. van den Brink AU - Marita Westhrin AU - Muhammad Zahoor AU - Siv H. Moen AU - Glenn Buene AU - Kristine Misund AU - Anne-Marit Sponaas AU - Qianli Ma AU - Anders Sundan AU - Richard WJ Groen AU - Tobias S. Slørdahl AU - Anders Waage AU - Therese Standal Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/02/22/2021.02.22.431638.abstract N2 - IL-32 is a non-classical cytokine expressed in cancers, inflammatory diseases and infections. IL-32 can have both extracellular and intracellular functions, and its receptor is not identified. We here demonstrate that endogenously expressed, intracellular IL-32 binds to components of the mitochondrial respiratory chain and promotes oxidative phosphorylation. Knocking out IL-32 in malignant plasma cells significantly reduced survival and proliferation in vitro and in vivo. High throughput transcriptomic and MS-metabolomic profiling of IL-32 KO cells revealed that loss of IL-32 leads to profound perturbations in metabolic pathways, with accumulation of lipids, pyruvate precursors and citrate, indicative of reduced mitochondrial function. IL-32 is expressed in a subgroup of multiple myeloma patients with an inferior prognosis. Primary myeloma cells expressing IL-32 were characterized by a plasma cell gene signature associated with immune activation, proliferation and oxidative phosphorylation. We propose a novel concept for regulation of metabolism by an intracellular cytokine and identify IL-32 as an endogenous growth and survival factor for malignant plasma cells. IL-32 is a potential prognostic biomarker and a treatment target in multiple myeloma.Competing Interest StatementThe authors have declared no competing interest. ER -