ERP129988 PRJEB45829 ena-STUDY-Klinikum rechts der Isar, II. Medizinische Klinik-21-06-2021-13:40:54:791-1043 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 that drives the G1/S cell cycle transition by means of deubiquitylating and stabilizing LIN28B. RNA-Seq analyses reveal a significant downregulation of MYC target genes upon OTUD6B and LIN28B downregulation. 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 genetic screening for DUB dependencies in MM, we here identify OTUD6B as a central vulnerability in MM that drives the G1/S cell cycle transition by means of deubiquitylating and stabilizing LIN28B in phosphorylation dependent manner. LIN28B regulates miRNA biogenesis and exerts high expression in embryonic stem cells that becomes re-established in certain tumors, including MM. RNA-Seq analyses of OTUD6B and LIN28B depleted RPMI8226 MM cells reveal a significant downregulation of MYC target genes in both conditions. 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 genetic screening for DUB dependencies in MM, we here identify OTUD6B as a central vulnerability in MM that drives the G1/S cell cycle transition by means of deubiquitylating and stabilizing LIN28B in phosphorylation dependent manner. LIN28B regulates miRNA biogenesis and exerts high expression in embryonic stem cells that becomes re-established in certain tumors, including MM. RNA-Seq analyses of OTUD6B and LIN28B depleted RPMI8226 MM cells reveal a significant downregulation of MYC target genes in both conditions. ENA-FIRST-PUBLIC 2022-10-10 ENA-LAST-UPDATE 2022-10-11