Altered nucleophosmin transport in acute myeloid leukaemia with mutated NPM1: molecular basis and clinical implications

Abstract

Nucleophosmin (NPM1) is a highly conserved nucleo-cytoplasmic shuttling protein that shows a restricted nucleolar localization. Mutations of NPM1 gene leading to aberrant cytoplasmic dislocation of nucleophosmin (NPMc þ ) occurs in about one third of acute myeloid leukaemia (AML) patients that exhibit distinctive biological and clinical features. We discuss the latest advances in the molecular basis of nucleophosmin traffic under physiological conditions, describe the molecular abnormalities underlying altered transport of nucleophosmin in NPM1-mutated AML and present evidences supporting the view that cytoplasmic nucleophosmin is a critical event for leukaemogenesis. We then outline how a highly specific immunohistochemical assay can be exploited to diagnose NPM1-mutated AML and myeloid sarcoma in paraffin-embedded samples by looking at aberrant nucleophosmin accumulation in cytoplasm of leukaemic cells. This procedure is also suitable for detection of haemopoietic multilineage involvement in bone marrow trephines. Moreover, use of immunohistochemistry as surrogate for molecular analysis can serve as first-line screening in AML and should facilitate implementation of the 2008 World Health Organization classification of myeloid neoplasms that now incorporates AML with mutated NPM1 (synonym: NPMc þ AML) as a new provisional entity. Finally, we discuss the future therapeutic perspectives aimed at reversing the altered nucleophosmin transport in AML with mutated NPM1.

Risk stratification using a new prognostic score for patients with secondary acute myeloid leukemia: results of the prospective AML96 trial

“…34 Additionally, extensive studies were able to demonstrate that NPM1 mutations are most relevant in younger AML patients with normal karyotype and less frequent in patients with karyotype abnormalities. 11,29,[34][35][36][37] Supporting this literature, we found mutation of NPM1 loses its significant influence on survival for patients older than 60 years of age in the multivariate analysis. As we are aware that all sAML patients in our study population as well as those in our test set were already treated risk adapted for age and cytogenetic risk, which is the international standard for AML therapy, it is difficult to determine whether this finding is an age-or a treatment-related effect.…”

Day 15 bone marrow driven double induction in young adult patients with acute myeloid leukemia: Feasibility, toxicity, and therapeutic results

“…Even though we cannot exclude that some patients would achieve CR without receiving DI, the 67% CR rate we observed is remarkable, if we consider that 65% of patients had unfavorable cytogenetics and no one of them were found positive for NMP1 mutation in absence of FLT3/ ITD mutations. Indirectly, our findings seem to confirm previous data suggesting that NPM11/FLT32 AML is associated with peculiar sensitivity to conventional chemotherapy, mainly to anthracyclines [34,35]. Such an assumption was recently suggested by data in young adults with AML, in whom intensifying induction therapy with a higher daily dose of daunorubicin improved the rate of CR and the duration of OS, when compared with the standard dose, only in patients with intermediate cytogenetics, in whom most NPM11 AML cases are found [5,6].…”

Mutual exclusion of ASXL1 and NPM1 mutations in a series of acute myeloid leukemias

“…The identification of mutations in several genes, such as NPM1 and FLT3, has revealed prognosis subgroups and modified their clinical management. 1 A better molecular characterization should further improve both the understanding of the physiopathology and the treatment of these leukemias.…”