METTL3-Mediated m6A Modification Controls Splicing Factor Abundance and Contributes to Aggressive CLL

RNA splicing dysregulation underlies the onset and progression of cancers. In chronic lymphocytic leukemia (CLL), spliceosome mutations leading to aberrant splicing occur in similar to 20% of patients. However, the mechanism for splicing defects in spliceosome-unmutated CLL cases remains elusive. Through an integrative transcriptomic and proteomic analysis, we discover that proteins involved in RNA splicing are posttranscriptionally upregulated in CLL cells, resulting in splicing dysregulation. The abundance of splicing complexes is an independent risk fac-tor for poor prognosis. Moreover, increased splicing factor expression is highly correlated with the abundance of METTL3, an RNA methyltransferase that deposits N6-methyladenosine (m6A) on mRNA. METTL3 is essential for cell growth in vitro and in vivo and controls splicing factor protein expression in a methyltransferase-dependent manner through m6A modifi cation-mediated ribosome recycling and decoding. Our results uncover METTL3-mediated m6A modifi cation as a novel regulatory axis in driving splicing dysregulation and contributing to aggressive CLL.SIGNIFICANCE: METTL3 controls widespread splicing factor abundance via translational control of m6A-modifi ed mRNA, contributes to RNA splicing dysregulation and disease progression in CLL, and serves as a potential therapeutic target in aggressive CLL.

Automated summary

RNA splicing dysregulation is a critical factor in the onset and progression of cancers, including chronic lymphocytic leukemia (CLL). Through transcriptomic and proteomic analysis, it has been found that proteins involved in RNA splicing are upregulated in CLL cells, leading to splicing dysregulation. The expression of splicing factors is highly correlated with the abundance of METTL3, an RNA methyltransferase that controls splicing factor protein expression through m6A modification-mediated ribosome recycling and decoding. The findings highlight the significance of METTL3-mediated m6A modification as a potential therapeutic target in aggressive CLL.