The OTUD6B-LIN28B-MYC axis determines the proliferative state in multiple myeloma

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Deubiquitylases (DUBs) are key regulators of protein stability and are implicated in cancer.
• Multiple myeloma is a malignancy dependent on the ubiquitin proteasome system, presenting a potential vulnerability.
• Targeting DUBs offers a strategy to destabilize oncoproteins, including those currently considered undruggable.

Purpose of the Study:

• To identify DUB vulnerabilities in multiple myeloma.
• To investigate the role of OTUD6B in driving the G1/S cell cycle transition in multiple myeloma.
• To elucidate the OTUD6B-LIN28B-MYC axis in multiple myeloma pathogenesis.

Main Methods:

• Screening for DUB vulnerabilities in multiple myeloma cell lines.
• Identifying cell cycle-specific substrates of OTUD6B.
• Assessing the impact of OTUD6B and LIN28B silencing on multiple myeloma growth in vivo.
• Correlating OTUD6B expression with patient outcomes in symptomatic multiple myeloma.

Main Results:

• OTUD6B was identified as an oncogene driving the G1/S transition in multiple myeloma.
• LIN28B was validated as a cell cycle-specific substrate of OTUD6B, and its stabilization promotes MYC expression.
• Silencing OTUD6B or LIN28B significantly inhibited multiple myeloma outgrowth in vivo.
• High OTUD6B expression correlated with disease progression and adverse outcomes in multiple myeloma patients.

Conclusions:

• OTUD6B acts as an oncogene in multiple myeloma by stabilizing LIN28B, which drives MYC expression and G1/S transition.
• The OTUD6B-LIN28B axis represents a novel therapeutic vulnerability in multiple myeloma.
• OTUD6B may mediate the transition from MGUS to symptomatic multiple myeloma and serves as a prognostic marker.