Abstract
Nucleophosmin (NPM1) gene mutations rarely occur in non-acute myeloid neoplasms (MNs) with <20% blasts. Among nearly 10,000 patients investigated so far, molecular analyses documented NPM1 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 NPM1-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 NPM1-mutated MNs with blast count <20%, since NPM1-mutated AML cases frequently present dysplastic features and multilineage bone marrow cells showing abnormal cytoplasmic NPM1 protein delocalization by immunohistochemical staining, therefore belonging to NPM1-mutated clone regardless of blast morphology. Further prospective studies are warranted to definitely assess whether NPM1 mutations may become sufficient to diagnose AML, irrespective of blast percentage.
Highlights
The nucleophosmin (NPM1) gene encodes an ubiquitous protein which physiologically shuttles between the nucleus and cytoplasm, acting as a molecular chaperone to establish multiple protein–protein interactions [1]
Itzykson et al observed that, not yet considered an acute myeloid leukemia (AML)-defining lesion, the presence of NPM1 mutation in chronic myelomonocytic leukemia (CMML) tends to be associated to an aggressive clinical course, suggesting that finding NPM1 mutations may favor a diagnosis of de novo AML exhibiting dysplastic features and monocytic differentiation, belonging to M4 or M5 AML subgroups according to former FAB classification, rather than CMML [90]
For younger and fit patients affected with higher risk myelodysplastic syndrome (MDS) or CMML, allogeneic hematopoietic stem cell transplantation (HSCT) is generally recommended, either upfront if bone marrow (BM) blast count is less than 10% or after cytoreductive treatment in cases with blast percentage >10%
Summary
The nucleophosmin (NPM1) gene encodes an ubiquitous protein which physiologically shuttles between the nucleus and cytoplasm, acting as a molecular chaperone to establish multiple protein–protein interactions [1]. The NPM1 gene translocations to different partner genes are implicated in the pathogenesis of several hematopoietic malignancies, including CD30-positive anaplastic large-cell lymphoma with t(2;5), the infrequent myelodysplasia/acute myeloid leukemia (MDS/AML) with t(3;5) and extremely rare cases of acute promyelocytic leukemia with t(5;17), resulting in the generation of NPM1–ALK, NPM1–MLF1 and NPM1–RARA fusion transcripts, respectively [2,3]. All these genetic alterations usually perturb the normal cellular traffic of NPM1 protein in malignant cells, but we will focus here on the biological and clinical significance of NPM1 gene mutations occurring in acute myeloid leukemia (AML) and other myeloid neoplasms [2,3,4,5]
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