Investigating the role of the m6A RNA methyltransferase METTL3 in Acute Myeloid Leukemia
N6-methyladenosine (m6A) is the most abundant dynamic mark of messenger RNA where it may affect most posttranscriptional steps in gene expression, including splicing, stability and translation. This modification is indispensable for cell viability and development, yet its role in cancer is still poorly understood.
In mammals, the writer of m6A is a nuclear multicomponent complex composed of two methyltransferases METTL3 and METTL14, and the regulatory protein WTAP. METTL3 is the catalytic component while METTL14 functions in structural stabilization and RNA substrate recognition. Notably, WTAP has been recently described as an oncogenic factor in acute myeloid leukemia (AML). Moreover, we have observed a general increase of METTL3 and METTL4 expression in AML, suggesting that their alteration might contribute to leukemogenesis.
Deregulation of the m6A complex in AML cell lines (our preliminary data), strongly induces apoptosis. Thus, a major aim of this proposal is to prove whether the inhibition of the formation of m6A modification could have therapeutic value in AML. Our preliminary data show that in AML cells the METTL3 catalytic component is mis-localized in the cytoplasm where it associates with translating ribosomes. Thus, indicating additional function for METTL3 independent from the nuclear methylation complex. Therein, it will be critical to establish if the phenotypes observed in AML cells are indeed methylation dependent and not due to secondary functions of the associated enzymes.
To address these questions, we propose the following aims: 1) To address the contribution of METTL3 catalytic activity in AML and normal CD34+ hematopoietic stem cells (HSC) proliferation and, 2) to assess the role of cytoplasmic METTL3 in AML cells.