Acute myeloid leukemia with mutated nucleophosmin (NPM1): Any hope for a targeted therapy?

Acute myeloid leukemia (AML) carrying nucleophosmin (NPM1) mutations displays distinct molecular and clinical–pathological features that led to its inclusion as provisional entity in 2008 WHO classification of myeloid neoplasms. Since NPM1 mutations behave as a founder genetic lesion in AML, they could be an attractive target for therapeutic intervention. Here, we discuss the potential for developing targeted therapies for NPM1-mutated AML with focus on: i) interfering with the abnormal traffic of the NPM1 leukemic mutant, i.e. its cytoplasmic dislocation; ii) disrupting the nucleolar structure/function by interfering with residual wild-type nucleophosmin and other nucleolar components acting as hub proteins; and iii) evaluating the activity of epigenetic drugs (e.g. 5-azacytidine) or agents acting on differentiation and apoptosis. As quantitative assessment of NPM1 mutated transcript copies now provides the means to measure minimal residual disease, we also discuss the potential for intervening in NPM1-mutated AML before overt hematological relapse occurs (so-called pre-emptive therapy).