Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biologic and clinical features

Abstract

The nucleophosmin (NPM1) gene encodes for a multifunctional nucleocytoplasmic shuttling protein that is localized mainly in the nucleolus. NPM1 mutations occur in 50% to 60% of adult acute myeloid leukemia with normal karyotype (AML-NK) and generate NPM mutants that localize aberrantly in the leukemic-cell cytoplasm, hence the term NPM-cytoplasmic positive (NPMc+ AML). Cytoplasmic NPM accumulation is caused by the concerted action of 2 alterations at mutant C-terminus, that is, changes of tryptophan(s) 288 and 290 (or only 290) and creation of an additional nuclear export signal (NES) motif. NPMc+ AML shows increased frequency in adults and females, wide morphologic spectrum, multilineage involvement, high frequency of FLT3-ITD, CD34 negativity, and a distinct gene-expression profile. Analysis of mutated NPM has important clinical and pathologic applications. Immunohistochemical detection of cytoplasmic NPM predicts NPM1 mutations and helps rationalize cytogenetic/molecular studies in AML. NPM1 mutations in absence of FLT3-ITD identify a prognostically favorable subgroup in the heterogeneous AML-NK category. Due to their frequency and stability, NPM1 mutations may become a new tool for monitoring minimal residual disease in AML-NK. Future studies should focus on clarifying how NPM mutants promote leukemia, integrating NPMc+ AML in the upcoming World Health Organization leukemia classification, and eventually developing specific antileukemic drugs.

Clinicopathologic analysis of acute myeloid leukemia arising from chronic myelomonocytic leukemia

“…This finding, as well as the rapid progression of NPM1-mutated chronic myelomonocytic leukemia patients to acute myeloid leukemia in our series and in another published series, 24 suggests that cases diagnosed as chronic myelomonocytic leukemia with an NPM1 mutation may actually represent early de novo acute myeloid leukemia exhibiting dysplastic features and monocytosis mimicking chronic myelomonocytic leukemia. 36 It may thus be useful to screen chronic myelomonocytic leukemia cases for NPM1 mutation and carefully follow cases with NPM1 mutation for possible rapid transformation to 'bona fide' acute myeloid leukemia.…”

Nucleophosmin mutations in acute myeloid leukemia: A tale of protein unfolding and mislocalization

“…3). 22,23 Although more than 50 mutations have been reported so far, the consequences at the protein level are similar in all cases. The reading frame is altered and this leads to a variant NPM1 protein that has a different sequence in the last seven residues and is four residues longer.…”

“…70 Moreover, NPM1 mutations: (i) are specific for AML (usually de novo type with normal karyotype), (ii) are mutually exclusive of AML with recurrent genetic abnormalities, and (iii) show distinct gene and microRNA profiles. 23,24,71,72 Notably, the small subset of leukemic stem cells isolated from these patients carry NPM1 mutations and cytosolic NPM1, recapitulating the original disease when transplantated in immunocompromised mice. 73,74 All these evidences point to NPM1 mutation as an early initiating event in AML 24 and make NPM1 an ideal target for therapy.…”

“…10,15,16,23,24 Here, we focus on the C-terminal domain of the protein. We describe its structure, interactions, known physiological functions, and how they are modified in the NPM1 leukemic mutants.…”

“…[22][23][24] NPM1 mutations are always heterozygous [22][23][24] and mutually exclusive with AML carrying recurrent genetic abnormalities. 26 Mutations cluster in the terminal exon (XII) of the NPM1 gene and consist in the duplication or insertion of small nucleotide stretches (Fig.…”