Mutant p53 : specific functions and role of inflammation in leukemia progression – MUTP53

Acute myeloid leukemia (AML) can occur secondary to myeloproliferative neoplasms (MPN). They are characterized by abnormalities of p53 axis in half of the cases. Majority of p53 mutants are missense mutants, with gain of functions effects well described in solid cancers but currently debated in the AML field. We developed mouse models of post-MPN AML harboring MPN-driver mutation (JAK2V617F) associated with p53 loss or mutants and observed specific features associated to the mutants, in particular decreased survival due to earlier AML onset. We also showed in another work using primary patients samples and mouse models that IFN-related inflammation leads to p53 clonal selection and AML progression in NMP.
The goal of the project is to decipher the new functions associated to the mutants, how this can lead to leukemic progression and the role of inflammation in this process.
We will first use several -omics techniques to identify new pathways and partners, specifically associated with p53 mutants. These analyses will be performed in erythro-megakaryocytic (E/MK) compartment as we showed that leukemic cells were amplified in these populations. New targets, pathways or partners will be then validated by functional studies using in vitro and in vivo models already established in the lab (cell lines, human primary samples, transgenic mice, patient derived xenografts).
We will also determine how p53 mutants can be selected and contribute to AML development in MPN background, upon 2 different inflammatory stimuli : poly(I:C) which mimics type 1 IFN pathway, and age. We will study mouse phenotype, as well as genetic instability and transcription upon inflammation in the various models.
Our study will be instrumental to understand physiopathological mechanisms linked to p53 mutants in AML, with the identification of new pathways/partners and the role of inflammation in that process. Our results could have broader relevance as they could be applicable to other secondary AML with TP53 mutations, as therapy related AML. Our findings could ultimately lead to better patients’ treatment, and to ameliorate the prognosis of these very serious diseases.