The role of transcription factor FOXM1 in multiple myeloma

Multiple myeloma (MM) is a blood cancer that affects elderly patients and, despite advances in research and clinical treatments, remains incurable. Research is ongoing to develop cures for MM, in part by understanding why some treatments work for some patients, and why some patients respond better to treatment than others. Both genetics, meaning mutations, and cell behavior influence MM treatment response. One cell behavior that varies is how much of each gene a MM cell makes. Overexpression of certain genes correlates with response to therapy and overall survival. Overexpression of the FOXM1 gene, which is subsequently translated into a protein that itself turns genes on and off, correlates with aggressive, drug-resistant MM and poor survival. How FOXM1 causes MM disease progression and drug resistance is not known, but understanding its function may help improve treatment.

The purpose of this study was to delete FOXM1 in human myeloma cell lines (HMCLs) to better understand its function. First, the amount of FOXM1 protein was measured in a panel of HMCLs. The DNA of the HMCLs with the most FOXM1 protein was edited using a cutting edge technique called CRISPR in order to block, or “knock out” (KO), FOXM1 protein production. HMCLs with no FOXM1 were tested for changes in cell growth and sensitivity to common MM treatment and compared to unedited HMCLs. Depletion of FOXM1 impaired the growth of the HMCLs and increased the response of the HMCLs to MM drugs. Finally, FOXM1 was reintroduced into the KO HMCLs to verify that the effect seen after KO was due to the absence of FOXM1. The HMCLs exhibited an increase in resistance to MM drugs upon FOXM1 reintroduction. These findings support a role for FOXM1 in MM disease progression and resistance to treatment.