Fonseca, Rafael

ABSTRACT Background Immunomodulatory agents (IMiDs) are a cornerstone in the successful management of multiple myeloma (MM). However, acquired IMiD resistance leading to disease relapses remains a major barrier. Hydrogen peroxide generation and oxidative stress are key mediators that determine IMiD's effectiveness in MM. Iron plays a key role in the generation of oxidative stress; therefore, cellular iron levels are tightly governed. FTH1 is the major iron storage protein that tightly regulates cellular iron availability. Hence, the present study is targeted to investigate the role of FTH1 in MM and IMiD resistance. Methods IMiD‐sensitive and IMiD‐resistant MM cells were analyzed for expression of iron‐metabolism genes. CRISPR‐cas9‐mediated knockout of FTH1 was performed and the after‐effects were assessed through multiple experiments. Results Initial analysis showed a positive correlation between FTH1 expression and IMiD resistance in MM cells. FTH1 ‐KO reduced IMiD sensitivity in the KMS11 cell line but had no effect on the RPMI8226 cell line. RNA‐seq data showed downregulation of ER‐stress and calcium signaling genes after FTH1 ‐KO. Further, KMS11‐ FTH1 KO cells exhibited lower intracellular ROS, labile‐iron, and mitochondrial superoxide levels along with increased CD63, suggesting activation of L‐ferritin secretory pathways. Conclusion Data reveals a link between FTH1 , labile iron, ROS, and IMiD resistance in MM cells.