<i>NPM1</i>-Mutated Myeloid Neoplasms with <20% Blasts: A Really Distinct Clinico-Pathologic Entity?

• Main Authors: Fabio Forghieri, Vincenzo Nasillo, Ambra Paolini, Francesca Bettelli, Valeria Pioli, Davide Giusti, Andrea Gilioli, Corrado Colasante, Gloria Acquaviva, Giovanni Riva, Patrizia Barozzi, Rossana Maffei, Leonardo Potenza, Roberto Marasca, Claudio Fozza, Enrico Tagliafico, Tommaso Trenti, Patrizia Comoli, Giuseppe Longo, Mario Luppi
• Format: Article
• Language: English
• Published: MDPI AG 2020-11-01
• Series: International Journal of Molecular Sciences
• Subjects: <i>NPM1</i> mutation; myelodysplastic syndromes; myelodysplastic/myeloproliferative neoplasms; chronic myelomonocytic leukemia; acute myeloid leukemia; leukemogenesis
• Online Access: https://www.mdpi.com/1422-0067/21/23/8975

Nucleophosmin (<i>NPM1</i>) gene mutations rarely occur in non-acute myeloid neoplasms (MNs) with <20% blasts. Among nearly 10,000 patients investigated so far, molecular analyses documented <i>NPM1</i> mutations in around 2% of myelodysplastic syndrome (MDS) cases, mainly belonging to MDS with excess of blasts, and 3% of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) cases, prevalently classified as chronic myelomonocytic leukemia. These uncommon malignancies are associated with an aggressive clinical course, relatively rapid progression to overt acute myeloid leukemia (AML) and poor survival outcomes, raising controversies on their classification as distinct clinico-pathologic entities. Furthermore, fit patients with <i>NPM1</i>-mutated MNs with <20% blasts could benefit most from upfront intensive chemotherapy for AML rather than from moderate intensity MDS-directed therapies, although no firm conclusion can currently be drawn on best therapeutic approaches, due to the limited available data, obtained from small and mainly retrospective series. Caution is also suggested in definitely diagnosing <i>NPM1</i>-mutated MNs with blast count <20%, since <i>NPM1</i>-mutated AML cases frequently present dysplastic features and multilineage bone marrow cells showing abnormal cytoplasmic NPM1 protein delocalization by immunohistochemical staining, therefore belonging to <i>NPM1</i>-mutated clone regardless of blast morphology. Further prospective studies are warranted to definitely assess whether <i>NPM1</i> mutations may become sufficient to diagnose AML, irrespective of blast percentage.