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"These results address the long‐standing questions in how far DUBs can serve as actionable therapeutic targets in cancer, particularly in patients with MM and how the UPS can contribute to the conversion of MGUS to MM.Targeting OTUD6B provides a strategy to activate let‐7 microRNAs via LIN28B destabilization to repress their targets, of which we show that MYC is the prominent determinant in MM."