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.
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 (Ianniello and Fatica, 2018; Ianniello et al., 2019). Growing evidence indicates that the targeting of the post-transcriptional reversible mRNA modification (RNA epigenetics or epitranscriptomics), which regulates the genomic output and mRNA function, could represent a central tool for the development of novel RNA-based drugs and therapies. In this context, different strategies focused to alter the post-transcriptional RNA modification status, targeting the RNA methyltransferase complex, may be relevant to disclose innovative and significant molecular pathways to target hematological malignancies.
This project will deepen our comprehension of chronic myeloid leukemia (CML) biology and has great potential to open novel windows of therapeutic intervention. In particular, resistance to the BCR-ABL tyrosine kinase inhibitor (TKI) remains a challenge for curing the disease in CML patients as leukemia cells may survive through BCR-ABL kinase activity-independent signal pathways. We believe that results obtained from our proposal will contribute to important advances in the search for novel therapeutic strategies for human CML resistant to TKI inhibitors. The ability to identify and modify the post-transcriptional RNA modification status by the use of selective compounds targeting the RNA methyltransferase complex may reveal possible future therapeutic applications for patient treatments. Therefore, based on results from this proposal, a patent might be filed fo therapeutic use of post-transcriptional RNA modification status through the use of selective compound targeting the RNA methyltransferase complex. In line with this, results of our studies may lead to possible commercial applications of the modification status of the transcriptome in the clinical setting.
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 levels, such as acute myeloid leukemia (AML).
The activities conducted in the context of this research project will be the starting point for the creation of significant intellectual property (patenting of new biological target for the design of compound potentially interesting for therapy). Along this line, the main results expected from this project are:
- Identification of novel therapeutic targets for pharmacological therapy (targets for drug screening and design) and biological therapy (small molecules-based therapy) for CML.
- Identification of new molecular pathways that could be explored as markers for diagnosis and/or prognosis of CML (diagnostic, prognostic array for the evaluation of the methylation status of specific RNA molecules).
Our technological advancement will be also 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 management and effectiveness of treatments of leukemia.
References:
Ianniello Z and Fatica A. N6-Methyladenosine Role in Acute Myeloid Leukaemia. Int J Mol Sci. 2018;19(8). pii: E2345.
Ianniello Z et al., 2019. N6-Methyladenosine (m6A): A Promising New Molecular Target in Acute Myeloid Leukemia. Front Oncol. 2019; 9:251.