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. The use ABL1 tyrosine kinase inhibitors (TKI) made CML a clinically manageable and a cured disease. However, in the majority of cases, treatment with TKIs is not curative and patients develop resistance. 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. In analogy with the changes that occur on chromatin, m6A in mRNA is installed by "writers", removed by "erasers" and can recruit specific "reader" proteins. 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 might play a relevant role also in CML.
In this research project, we aim at investigating the role of m6A CML cells. In particular, we will: 1) characterize the function of the m6A writers and readers; and 2) develop lead compounds for interfering with the m6A activity.
The overall remit of the project is to provide a comprehensive understanding of the role of m6A writers in CML and to characterize new relevant pathways in leukaemia biology. We also expect to identify novel molecules that inhibits m6A activity for developing new therapeutic strategies.