The feed-forward loop between YB-1 and MYC is essential for multiple myeloma cell survival

Area of Science:

• Molecular Biology
• Oncology
• Cancer Research

Background:

• Y-box binding protein 1 (YB-1) is a translational regulator implicated in multiple myeloma (MM).
• YB-1 was previously suggested to enhance MYC mRNA translation via an internal ribosome entry segment (IRES) mutation.

Purpose of the Study:

• To investigate the mechanism of YB-1-mediated MYC translation in MM.
• To determine the clinical relevance of YB-1 and MYC co-expression in MM.
• To explore the therapeutic potential of targeting the YB-1/MYC axis in MM.

Main Methods:

• Analysis of YB-1/MYC mutation status in MM patients and cell lines.
• Immunohistochemical staining for MYC and YB-1 in malignant plasma cells.
• YB-1 knockdown experiments in human MM cell lines (HMCLs).
• MYC knockdown and activation experiments in HMCLs and mouse embryonic fibroblasts (MEFs).

Main Results:

• The previously reported IRES mutation was absent in 87 MM patients and HMCLs.
• Positive MYC staining correlated with YB-1 co-expression, increasing in extramedullary MM.
• YB-1 knockdown reduced MYC protein and mRNA in polysomal fractions.
• MYC knockdown decreased YB-1 levels, while MYC activation increased YB-1 mRNA.
• Perturbation of the MYC/YB-1 circuit induced apoptosis in HMCLs.

Conclusions:

• YB-1 enhances MYC translation independently of the IRES mutation.
• MYC and YB-1 form a co-regulatory circuit involving both transcriptional and translational control.
• The MYC/YB-1 axis is crucial for MM cell survival.
• Targeting YB-1/mRNA interactions represents a novel therapeutic strategy for MM drug development.