biostudies-literaturePaulmann CDeutsche ForschungsgemeinschaftEuropean Research CouncilDeutsche Krebshilfee110871https://www.ebi.ac.uk/biostudies/studies/S-EPMC9574752biostudies-literatureUnknown41(20)Deubiquitylases (DUBs) are therapeutically amenable components of the ubiquitin machinery that stabilize substrate proteins. Their inhibition can destabilize oncoproteins that may otherwise be undruggable. Here, we screened for DUB vulnerabilities in multiple myeloma, an incurable malignancy with dependency on the ubiquitin proteasome system and identified OTUD6B as an oncogene that drives the G1/S-transition. LIN28B, a suppressor of microRNA biogenesis, is specified as a bona fide cell cycle-specific substrate of OTUD6B. Stabilization of LIN28B drives MYC expression at G1/S, which in turn allows for rapid S-phase entry. Silencing OTUD6B or LIN28B inhibits multiple myeloma outgrowth in vivo and high OTUD6B expression evolves in patients that progress to symptomatic multiple myeloma and resThe EMBO journalThe OTUD6B-LIN28B-MYC axis determines the proliferative state in multiple myeloma.PMC9574752682473BA 2851/6‐170114425360372040‐SFB 1335Spallek RKronke JWirth MKeller USchaffer IPaulmann CEngleitner TRudelius MKossatz SWalzik MBassermann FOllinger RHeider MZecha JRad RKarpiuk OKuster BKlaeger SfalseThe OTUD6B-LIN28B-MYC axis determines the proliferative state in multiple myeloma.Deubiquitylases (DUBs) are therapeutically amenable components of the ubiquitin machinery that stabilize substrate proteins. Their inhibition can destabilize oncoproteins that may otherwise be undruggable. Here, we screened for DUB vulnerabilities in multiple myeloma, an incurable malignancy with dependency on the ubiquitin proteasome system and identified OTUD6B as an oncogene that drives the G1/S-transition. LIN28B, a suppressor of microRNA biogenesis, is specified as a bona fide cell cycle-specific substrate of OTUD6B. Stabilization of LIN28B drives MYC expression at G1/S, which in turn allows for rapid S-phase entry. Silencing OTUD6B or LIN28B inhibits multiple myeloma outgrowth in vivo and high OTUD6B expression evolves in patients that progress to symptomatic multiple myeloma and res2022-01-01T00:00:00Z2022 Oct2026-05-28T00:42:53.842Z2025-04-04T23:36:39.503ZS-EPMC95747523605927410.15252/embj.2022110871