Determining the Roles of Ero1‐α and Ero1‐β in Progression of MM

Multiple myeloma (MM) is a treatable but incurable hematological malignancy. Drug resistance continues to limit the success of therapeutic strategies to treat MM. Thus, clinical data continues to indicate that new treatment strategies are required to treat drug resistant disease. Disulfide bond formation is critical for the folding, stability and function of newly synthesized secretory and membrane proteins residing in the endoplasmic reticulum (ER). Ero1‐α and Ero1‐β are two flavoprotein isomers which can form de‐novo disulfide bridges representing a critical initial step in disulfide bond formation of target proteins. In addition, both isoforms have similar molecular weight, amino acid distribution and a conserved flavin adenine dinucleotide (FAD) binding domain. Despite the structural similarities, the function of Ero1‐α and Ero1‐β on MM is currently unknown. We used genetic strategies to determine the roles of Ero1‐α and Ero1‐β on growth and drug resistance in MM model systems. We found that reducing the expression of Ero1‐α inhibits cell proliferation. Conversely, overexpression of Ero1‐α enhanced tumor engraftment in xenograft model. In contrast, reducing the expression of Ero1‐β increased cell proliferation and was sufficient to confer resistance to FDA approved drugs for the treatment of MM with distinct mechanisms of actions, (bortezomib (BTZ), dexamethasone (DEX) and LBH589 (LBH)). The resistance to DEX treatment was over 400 fold in MM cells with reduced Ero1‐β levels. This finding correlated with a dramatic reduction in glucocorticoid receptor (GR) that was regulated by transcriptional and post‐transcriptional mechanisms. Together, these data indicate the Ero1‐α and Ero1‐β have divergent mechanism in MM and provide rationale to develop specific inhibitors for targeting Ero1‐α to inhibit MM growth.