A novel peptidylarginine deiminase 4 (PAD4) inhibitor BMS-P5 blocks formation of neutrophil extracellular traps and delays progression of multiple myeloma

Multiple myeloma (MM) is a plasma cell malignancy that grows in the bone marrow (BM). The major population of cells in the BM is represented by neutrophils and they can form neutrophil extracellular traps (NETs). Here, we investigated whether MM cells induce NET formation and whether targeting this process would delay MM progression. We demonstrated that murine and human MM cells stimulate citrullination of histone H3 and NET formation by neutrophils and that this process is abrogated by pharmacological targeting of peptidylarginine deiminase 4 (PAD4) with a novel specific small molecule inhibitor BMS-P5. Administration of BMS-P5 to MM-bearing mice delays appearance of symptoms and disease progression. Taken together, our data demonstrate that targeting PAD4 may be beneficial for treatment of MM.