Defining the RNA Modification Landscape of Multiple Myeloma Reveals METTL3-Dependent m⁶A Regulation of NEAT1

Area of Science:

• Molecular Biology
• Epigenetics
• Cancer Research

Background:

• RNA modifications regulate gene expression, but their role in multiple myeloma (MM) is poorly understood.
• N6-methyladenosine (m⁶A) is the most prevalent mRNA and long noncoding RNA (lncRNA) modification, influencing RNA processing, stability, and translation.
• The contribution of m⁶A-modified lncRNAs to MM pathogenesis remains unclear.

Purpose of the Study:

• To define the RNA modification landscape in multiple myeloma.
• To investigate the role of m⁶A-modified lncRNAs, specifically NEAT1, in MM.
• To identify potential therapeutic targets within the epitranscriptome of MM.

Main Methods:

• Combined mass spectrometry, Nanopore Direct RNA sequencing, and methylated RNA immunoprecipitation sequencing to map RNA modifications.
• Validated m⁶A sites on the lncRNA NEAT1.
• Utilized functional studies and single-cell RNA sequencing to assess NEAT1's role in MM cell viability and identify its regulators.

Main Results:

• Identified 20 RNA modification types and over 15,000 m⁶A sites, including sites on 2,398 lncRNAs.
• Confirmed m⁶A modification on the lncRNA NEAT1, regulated by METTL3.
• Demonstrated that demethylation of a NEAT1 m⁶A site reduces MM cell viability, with NEAT1 enriched in malignant plasma cells.

Conclusions:

• m⁶A-modified lncRNAs are key regulators of multiple myeloma biology.
• NEAT1 is an epitranscriptomically controlled driver of MM cell survival.
• Targeting RNA modifications presents a potential therapeutic strategy for MM.