METTL3 Controls Splicing Factor Abundance and Aids Progression in CLL

Yiming Wu, PhD

METTL3-mediated N6-methyladenosine (m⁶A) modification contributes to chronic lymphocytic leukemia (CLL) progression and is associated with negative clinical outcomes in patients with CLL who do not have spliceosome mutations, according to Yiming Wu, PhD.

In a study investigating the effects of METTL3-mediated m⁶A modification on splicing factor abundance in CLL, Wu and colleagues found that the protein METTL3 post-transcriptionally upregulates splicing factors in CLL through m⁶A-mediated translational control. Furthermore, in vitro and in vivo analyses showed that METTL3 expression is associated with CLL cell survival and thus represents a potential target for CLL management.¹

“We found the upregulated circuitry of METTL3 and RNA splicing. Additionally, high METTL3 expression is associated with poor outcomes in CLL, so it could be a therapeutic target for the treatment of patients with CLL,” Wu said in an interview with OncLive^® during the 2023 AACR Annual Meeting.

In the interview, Wu discussed the rationale for studying splicing defects in patients with CLL without spliceosome mutations, shared key findings from this study, and emphasized how these findings support further research with METTL3 in CLL and other hematologic malignancies with RNA splicing dysregulation.

Wu is a postdoctoral fellow in the Department of Systems Biology at City of Hope in Duarte, California.

OncLive: How did studying splicing defects lead to the discovery of METTL3 as a potential therapeutic target in CLL?

Wu: Splicing defects are a common feature of CLL, but only 20% of patients have spliceosome mutations. We wanted to study the rest of the patients who have splicing defects but don’t have the spliceosome mutation.

Our study found that METTL3 could regulate RNA splicing in CLL. Through the omics analysis we conducted using the patient samples, we found that the splicing factors were post-transcriptionally upregulated in the patients, and METTL3 translationally regulated spicing factors through m⁶A modification. Our study highlights that m⁶A modification plays an important role [in that it] contributes to the splicing defects in spliceosome-unmutated CLL cases. In addition, we found that high METTL3 protein expression is associated with the outcomes of patients with CLL, which provided the rationale for us to target METTL3 as a novel strategy for the treatment of patients with CLL.

What methods were used in this research?

In the first part, we used the omics analysis, [which included] RNA sequencing and proteomics, in patients with CLL, and we used normal B cells as a control. From this omics analysis, we found that splicing factors are post-transcriptionally upregulated. Then, we wanted to [determine] the regulators for the splicing factors in this disease. We did a series of in vitro and in vivo studies, which found that METTL3 is the key regulator of the upregulated splicing factors.

What findings from this study were presented at AACR?

We found that splicing factors are post-transcriptionally upregulated in CLL and that METTL3 could translationally regulate splicing factors through m⁶A modification. More importantly, we found that METTL3 could be a potential target for the treatment of patients with CLL.

Are these findings in line with what previous CLL research has shown?

Previously, [researchers] mainly focused on the spliceosome mutations, and [to our knowledge], this is the first time we’ve found that spliceosome abundance could also contribute to splicing defects in the disease. It’s also the first time we’ve found that this could be regulated by the RNA epigenetics circuitry. 

What next steps would you like to see taken with this research?

We want to further study how METTL3 affects the [onset] and progression of CLL using additional mouse models. [We also want] to figure out whether METTL3 could be a true therapeutic target for the treatment of patients with CLL. Our ultimate goal is to translate our findings [so they can benefit clinical practice].

[In addition], [since this is] useful in the treatment of patients with acute myeloid leukemia, other [patients may] also benefit from this research. [It may be] easier to take METTL3 as a targeted CLL treatment since some small-molecule inhibitors have already been developed to target METTL3 [in the treatment of patients with] other diseases.

Reference

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