Here, our data suggest that (1) p53 may be un-responsible for the MPN progressive phenotype, despite a large set of gene expression deregulations being affected by Trp53 inactivation; (2) Trp53 inactivation facilitates clonal progression; and (3) Trp53 inactivation induces resistance to interferon-α (IFN-α) therapy in MPN but is not sufficient to induce direct transformation of chronic-phase MPN, leading us to hypothesize that acute transformation of such pathologies requires more than two oncogenic hits. Here, TP53 is linked to myeloproliferative neoplasm.