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MM cell lines also express high levels of MIF, and knocking out MIF made them more sensitive to proteasome inhibitor (PI)-induced apoptosis not observed with other chemotherapy drugs. Mechanistic studies showed that MIF protects MM cells from PI-induced apoptosis by maintaining mitochondrial function via suppression of superoxide production in response to PIs. Specifically, MIF, in the form of a homotrimer, acts as a chaperone for superoxide dismutase 1 (SOD1) to suppress PI-induced SOD1 misfolding and to maintain SOD1 activity. MIF inhibitor 4-iodo-6-phenylpyrimidine and homotrimer disrupter ebselen, which do not kill MM cells, enhanced PI-induced SOD1 misfolding and loss of function, resulting in significantly more cell death in both cell lines and primary MM cells. More importantly, inhibiting MIF activity in vivo displayed synergistic antitumor activity with PIs and resensitized PI-resistant MM cells to treatment. In support of these findings, gene-profiling data showed a significantly negative correlation between MIF and SOD1 expression and response to PI treatment in patients with MM. This study shows that MIF plays a crucial role in MM sensitivity to PIs and suggests that targeting MIF may be a promising strategy to (re)sensitize MM to the treatment.<\/jats:p>","DOI":"10.1182\/blood.2020005795","type":"journal-article","created":{"date-parts":[[2020,6,25]],"date-time":"2020-06-25T02:49:38Z","timestamp":1593053378000},"page":"2557-2573","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":57,"title":["MIF as a biomarker and therapeutic target for overcoming resistance to proteasome inhibitors in human myeloma"],"prefix":"10.1182","volume":"136","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6141-0068","authenticated-orcid":false,"given":"Qiang","family":"Wang","sequence":"first","affiliation":[{"name":"Center for Translational Research in Hematological Malignancies, Houston Methodist Cancer Center\/Houston Methodist Research Institute, Houston, 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