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.