METTL3 controls splicing factor abundance via N6-methyladenosine (m6A) mRNA modification and contributes to progression of chronic lymphocytic leukemia (CLL), according to research published in Blood Cancer Discovery. The findings suggest METTL3 could be a potential therapeutic target for CLL treatment.
“Mutations of splicing factors are present in only about 20% of CLL samples and cannot fully explain the general splicing defects observed in this disease,” the study authors explained in their report.
The researchers conducted an integrative transcriptomic and proteomic analysis to discover proteins involved in RNA splicing that are upregulated in CLL cells. They used both human-derived B cells, from healthy donors and patients with CLL, and murine models to characterize the molecular mechanism underlying splicing dysregulation in CLL.
The study demonstrated that the abundance of splicing complexes is an independent risk factor for poor prognosis, with patients with a high abundance having a lower probability of survival than those with low abundance. Further analysis revealed that increased expression of splicing factors expression was highly correlated with the abundance of METTL3, an RNA methyltransferase that m6A on mRNA, and higher METTL3 protein expression was associated with a shorter time to first therapy.
The researchers then demonstrated that in vitro depletion of METTL3 led to a greater growth disadvantage in CLL cells than in normal B cells. In mouse models, they showed that METTL3 is essential for cell growth in mature B-cell leukemia and lymphoma and controls splicing factor protein expression by modulating m6A.
“[Our results] uncover novel mechanisms that METTL3 utilizes to control the translation of splicing factors in a site-dependent fashion, which includes promoting fast ribosome recycling via m6A at stop codon regions to enhance translation and increasing ribosome pausing via m6A at [coding sequence] regions to perturb ribosomal elongation along transcripts and slow mRNA translation,” explained the authors. “Taken together, the evidence supports that METTL3 is essential to cell growth in mature B-cell leukemia
and lymphoma and is a potential therapeutic target for CLL treatment.”
Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, or device companies. Please see the original reference for a full list of authors’ disclosures.
Wu Y, Jin M, Fernandez M, et al. METTL3-Mediated m6a modification controls splicing factor abundance and contributes to aggressive CLL. Blood Cancer Discov. 2023;4(3):228-245. doi:10.1158/2643-3230.BCD-22-0156