Periodic Reporting for period 1 - PMLingAML (Using PML nuclear body biology to identify potential AML treatment targets)
Reporting period: 2020-12-17 to 2022-12-16
Acute myeloid leukaemias (AMLs) are cancers of the haematopoieic tissue (blood and bone marrow), and they are the most common type of acute leukaemias in adults. Acute myeloid leukaemias are heterogeneous diseases characterized by the abnormal clonal proliferation of hematopoietic stem and progenitor cells.
NPM1 is mutated in up to 35% of all acute myeloid leukaemia cases, and yet, its functions, such as in regulation of DNA repair, are still mostly unknown. However, the disruption of DNA damage repair could be one of the main causes for the acquisition of cooperative mutations, which lead to a severe reduction in the overall survival of patients with NPM1-mutated acute myeloid leukaemias. Understanding the molecular mechanisms of the initiation and development of acute myeloid leukaemia represents an important challenge which may lead to the identification of new therapeutic strategies.
NPM1 is mutated in up to 35% of all acute myeloid leukaemia cases, and yet, its functions, such as in regulation of DNA repair, are still mostly unknown. However, the disruption of DNA damage repair could be one of the main causes for the acquisition of cooperative mutations, which lead to a severe reduction in the overall survival of patients with NPM1-mutated acute myeloid leukaemias. Understanding the molecular mechanisms of the initiation and development of acute myeloid leukaemia represents an important challenge which may lead to the identification of new therapeutic strategies.
One common consequence of NPM1 mutations is the aberrant cytoplasmic accumulation of the NPM1 oncoprotein (NPM1c+). NPM1c+ acute myeloid leukaemia has a favourable prognosis and is highly responsive to induction therapy, while co-occurring mutations, such as FLT3-ITD, provoke a severe reduction in the overall survival. Moreover, NPM1c+ mutants represent tumour-initiating events. NPM1 is involved in ribosome biogenesis and centrosome duplication. However, NPM1 may have an additional role in the maintenance of genomic stability by regulating DNA single-strand break repair through the base excision repair (BER) pathway. BER is a major mechanism to resolve DNA single-strand breaks, which represents around 75% of all DNA lesions per cell per day. Thus, dysregulation of this DNA damage repair pathway could be one of the main causes for the acquisition of additional cooperative mutations, which are essential for NPM1c+-driven leukaemogenesis. Therefore, to assess the importance of NPM1 in the BER pathway, we performed state-of-the-art functional assays in primary cells, which allow the quantification of the efficiency of this repair pathway.
PML nuclear bodies are dynamic multiprotein complexes involved in a wide range of cellular functions, in association with ~100 proteins, including NPM1 partners such as p53 and MDM2. Since we previously demonstrated the significant contribution of PML nuclear bodies to DNA double-strand break repair (HR and NHEJ), we questioned the consequence of PML nuclear body disruption on the BER pathway using our published knock-in mouse model (PML-C62A/C65A).
PML nuclear bodies are dynamic multiprotein complexes involved in a wide range of cellular functions, in association with ~100 proteins, including NPM1 partners such as p53 and MDM2. Since we previously demonstrated the significant contribution of PML nuclear bodies to DNA double-strand break repair (HR and NHEJ), we questioned the consequence of PML nuclear body disruption on the BER pathway using our published knock-in mouse model (PML-C62A/C65A).
Although NPM1 has been identified more than two decades ago as one of the main oncogenes in acute myeloid leukemia, the lack of targeted therapy prompts for innovative research strategies. We are therefore convinced that our work on NPM1-related functions and on its oncogenic activity will be highly informative, thus leading to the emergence of novel hypothesis and consequently to novel treatment advancement.