Role of m6A RNA modification in acute myeloid leukemia
N6-methyladenosine (m6A) is the most abundant internal modification of the messenger RNA in eukaryotes. The m6A modification on mRNA functions as a dynamic mark that may control every aspect of its life, including splicing, stability and translation. In mammals, the writer of m6A is a nuclear multicomponent complex composed of two methyltransferases METTL3 and METTL14, and the regulatory protein WTAP. Post-transcriptional m6A RNA modification is indispensable for cell viability and development, yet its role in cell differentiation and disease are still poorly understood. Ineffective differentiation in one or more blood lineages is a hallmark of acute myeloid leukemia (AML) whereby the developmental program of myeloid cells is arrested. Notably, WTAP has been recently described as an oncogenic factor in AML, suggesting that alteration in the epitranscriptome might contribute to leukemogeneis. Our research interests are focused in defining the roles of m6A RNA modification in normal and abnormal differentiation of myeloid cells (granulocytes and monocytes) in order to understand how this modification is involved in the alternative control between cell growth and differentiation. In particular, we want to i) investigate the role of m6A modification in AML cells differentiation by knocking down writers, erasers and readers of m6A and by assessing its contribution to AML cell differentiation; ii) identify the RNA targets (coding and non-coding) of this modification with a potential role in AML cell growth and differentiation; iii) purify the METTL complex from AML cells in order to identify, if any, specific regulatory proteins.
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