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).
