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.
Our proposal focuses on an entirely new area of cancer research, the field of RNA chemical modifications, which appear to play a crucial role in leukaemogenesis. This project will deepen our comprehension of chronic myeloid leukemia (CML) biology. The advancement of knowledge in RNA epigenetics will provide useful information to develop a higher level of knowledge on CML tumorigenesis for the identification of innovative tools or targets to design novel therapeutic strategies. Our results will promise a significant reinforcement of the capability to address not only a specific therapeutic strategy for CML but also to other malignancies characterized by aberrant m6A and MYC levels, such as acute myeloid leukemia (AML).
The main results expected from this project are:
- Novel insight on the oncogenic function of MYC and on the connection between MYC, m6A modification and translation in CML.
-Identification of new molecular pathways that could be explored as markers for diagnosis and/or prognosis of CML.
Our advancement will be shared with the international scientific community, to provide a molecular and biological advance that is strongly needed in this field of cancer research, and to guarantee important improvements in the understanding of leukemia.