Ricerc@Sapienza

Chronic Myeloid leukaemia (CML) is a hematopoietic neoplasm characterized by the clonal expansion of myeloid cells. CML is associated in about 95% of patients with the production of the oncogenic BCL-ABL1 fusion gene. In CML, the BCR-ABL aberrant kinase activity induces MYC transcription and translation, and the oncogenic activity of BCR has been shown to depend on the MYC gene. Recently, chemical modification of RNA has emerged as a new mechanism of gene expression regulation. Among many, N6-methyladenosine (m6A) influences almost every stage of mRNA metabolism and accumulating evidence indicates a strong correlation between aberrant cellular m6A level and leukaemia. The first identified METTL3/METTL14 m6A modifying complex has been shown to play critical roles in acute myeloid leukemia (AML) survival and our preliminary data shows that it plays a relevant role also in CML. METTL3 is present on the chromatin of K562 cells with MYC and, more importantly, METTL3 was found as MYC interactor in large proteomic interactome study. Therein, we speculate that METTL3 can be a mediator of MYC oncogenic activity by allowing high levels of m6A modification and, eventually, efficient translation of MYC-transcribed genes to sustain translational potential of CML cells.
In this research project, we proposed to assess the impact of m6A modification mediated by METTL3 on the translation of MYC-regulated genes. The overall remit of the project is to characterize new relevant pathways in CML biology.