The balance between proliferation and differentiation is the key question in cancer progression. In particular, in myeloid cells, leukemiogenesis can be regarded as a block of cell differentiation leading to an uncontrolled growth with devastating consequences. On this regard, Acute myeloid leukemia (AML) is a clonal hematopoietic disorder resulting from genetic alterations in normal hematopoietic stem cells. These alterations disrupt normal differentiation and/or cause excessive proliferation of abnormal immature leukemic cells known as blasts. In this context, Adenosine deaminases acting on RNA (ADARs) can play some role as we have recently contributed to show. In more details, we have observed that ADAR1 enzyme is involved in the proliferation of leukemic cells. ADAR2, on the contrary, is expressed exclusively when the cells are induced to differentiate. However, their specific function in myeloid cell maturation remains to be defined. Here, we will continue our research by focusing on 1) the specific role played by the ADAR2 in the myeloid cell differentiation; 2) to analyse the homolog gene family member A (RhoA), we have identified in our previous work as target of the ADARs and which is edited in four positions during myeloid cell differentiation. Since these positions appear to play a role in splicing and therefore be relevant in producing different forms of RhoA , we will proceed in identifying the difference in the activity of RhoA before and after the editing process.
The scientific impact of this project is very high because the functional role of RNA editing in normal and pathological conditions is still largely unknown, although an increasing number of evidence suggests its crucial role in physiological conditions, as well as its involvement in various diseases, including cancer (6). In particular, the A-to-I deamination is extraordinarily abundant in the human transcriptome, compared to that of other mammals, for a total of several hundred thousand sites (4). Furthermore, a genome-wide association study of RNA editing A-I in acute myeloid leukemia has never been conducted to elucidate the molecular mechanisms underlying its functional role.
The results of the project could have a high scientific impact as they would allow us to extend our knowledge on the function of the ADARs enzymes, to identify relevant substrates in the regulation of cell proliferation / differentiation in myeloid leukemia and to design new drugs potentially able to interfere with the control of the maturation of leukemic cells.
Whether a specific ADAR enzyme or an editing substrate will be identified as a key component of the transition from normal to pathological myeloid differentiation, this could have an essential influence on research, diagnosis and clinical therapy.
Furthermore, the elucidation of the role of the RNA editing process in AML, including the identification of new molecular "pathways" that could be relevant in other types of cancer, provides a significant socio-economic impact due to the possibility of generating new approaches to therapy.
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