Dr Wu on the Role of METTL3-Mediated m6A Modification in CLL Progression

Yiming Wu, PhD, postdoctoral fellow, associate professor, Department of Systems Biology, City of Hope discusses a study identifying METTL3-mediated N6-methyladenosine (m6A) modification as a key translational regulator of splicing factors, and how this mechanism contributes to the progression of chronic lymphocytic leukemia (CLL).

It is known that RNA splicing dysregulation has a role in the onset and progression of tumors, such as CLL. However, the cause of such defects in spliceosome-unmutated CLL is poorly understood. By utilizing an integrative transcriptomic and proteomic analysis of primary CLL samples, high post-transcriptional expression of the spliceosome protein was found to be associated with these splicing defects, Wu begins. Therefore, a study was conducted to identify potential regulators of spliceosome expression.

Upregulation of the RNA methyltransferase METTL3 was found to positively correlate with a majority of detected splicing factors, and was associated with poorer clinical outcomes, Wu reports. This indicates that METTL3 translationally controls splicing factors through its modification of m6A on mRNA, Wu says.

Both in vitro and in vivo studies also showed that METTL3 played a major role in CLL growth. Knockout and pharmaceutical inhibition of METTL3 resulted in decreased cell growth and splicing factor overexpression. Lastly, an integrated Ribo-seq, RNA-seq, and MeRIP-seq was performed on CLL cells with or without METTL3. This revealed that METTL3 knockout substantially decreased efficiency in the RNA splicing pathway.

Overall, these data suggest that CLL could be regulated by RNA epigenetic mechanisms, and that METTL3 may be a potential target for the development of future therapies in CLL, Wu concludes.