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 

translationally controls splicing factors through its modification of m6A on mRNA, Wu says.

Both in vitro and in vivo studies also showed that 

played a major role in CLL growth. Knockout and pharmaceutical inhibition of 

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 

 knockout substantially decreased efficiency in the RNA splicing pathway.

Overall, these data suggest that CLL could be regulated by RNA epigenetic mechanisms, and that 

 may be a potential target for the development of future therapies in CLL, Wu concludes.

Videos

Yiming Wu, PhD, discusses a study identifying METTL3-mediated N6-methyladenosine modification as a key translational regulator of splicing factors, and how this mechanism contributes to the progression of chronic lymphocytic leukemia.
 

Yiming Wu, PhD

Articles

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