Multiple myeloma (MM) is the second most common hematological malignancy with poor outcome. Despite high sensitivity towards ubiquitin-proteasome-system (UPS) inhibitory therapies, the role of Deubiquitylases (DUBs) in MM pathophysiology and therapy has remained elusive. Starting from genetic screening for DUB dependencies in MM, we here identify OTUD6B as a central vulnerability in MM.. The OTUD6B-LIN28B-MYC axis determines cell cycle progression in multiple myeloma

Deubiquitylases (DUBs) remove ubiquitin from proteins. In the context of cancer, their inhibition can induce the degradation of oncoproteins, that may otherwise be “undruggable”. Multiple myeloma (MM) is the second most common hematological malignancy with poor outcome and high sensitivity towards ubiquitin-proteasome-system (UPS) inhibitory therapies. However, the role of DUBs in MM pathophysiology and therapy has remained elusive. Starting from a pooled CRISPR/Cas9-drop out screen for DUB dependencies in the MM cell line MM1.S, we here identify OTUD6B as a central vulnerability in MM.