Late relapse of acute myeloid leukemia with mutated NPM1 after eight years: evidence of NPM1 mutation stability

Meloni, G.; Mancini, Marco; Gianfelici, Valentina; Martelli, Maria Paola; Foa, R.; Falini, B.

doi:10.3324/haematol.000059

Cited by 29 publications

(20 citation statements)

References 6 publications

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“…34,35 Thus, all the evidences to date point to natural selection of a mutational event on the basis of its ability to promote cytoplasmic dislocation of the resulting protein, pointing to this event as critical for leukaemogenesis. 13 On the other hand, as NPM1 mutations in AML patients are always heterozygous and never co-exist with uniparental disomy 13,36 or deletion of the wild-type allele, a fraction of wildtype NPM1 seems needed for the survival of leukaemic cells.…”

Section: Discussionmentioning

confidence: 99%

A dose-dependent tug of war involving the NPM1 leukaemic mutant, nucleophosmin, and ARF

et al. 2008

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In acute myeloid leukaemia (AML), nucleophosmin-1 (NPM1) mutations create a nuclear export signal (NES) motif and disrupt tryptophans at NPM1 C-terminus, leading to nucleophosmin accumulation in leukaemic cell cytoplasm. We investigated how nucleophosmin NES motifs (two physiological and one created by the mutation) regulate traffic and interaction of mutated NPM1, NPM1wt and p14 ARF . Nucleophosmin export into cytoplasm was maximum when the protein contained all three NES motifs, as naturally occurs in NPM1-mutated AML. The two physiological NES motifs mediated NPM1 homo/ heterodimerization, influencing subcellular distribution of NPM1wt, mutated NPM1 and p14 ARF in a 'dose-dependent tug of war' fashion. In transfected cells, excess doses of mutant NPM1 relocated completely NPM1wt (and p14 ARF ) from the nucleoli to the cytoplasm. This distribution pattern was also observed in a proportion of NPM1-mutated AML patients. In transfected cells, excess of NPM1wt (and p14 ARF ) relocated NPM1 mutant from the cytoplasm to the nucleoli. Notably, this distribution pattern was not observed in AML patients where the mutant was consistently cytoplasmic restricted. These findings reinforce the concept that NPM1 mutants are naturally selected for most efficient cytoplasmic export, pointing to this event as critical for leukaemogenesis. Moreover, they provide a rationale basis for designing small molecules acting at the interface between mutated NPM1 and other interacting proteins.

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Section: Discussionmentioning

confidence: 99%

A dose-dependent tug of war involving the NPM1 leukaemic mutant, nucleophosmin, and ARF

et al. 2008

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“…Secondariness of chromosomal aberrations in NPM1-mutated AML is in line with the growing body of evidence that NPM1 mutation is a founder genetic lesion in AML, as supported by the following observations: (1) cytoplasmic mutated nucleophosmin is specific for AML 1,30,31 and clinically shows close association with AML of de novo origin 1,32-34 ; (2) NPM1 mutations are mutually exclusive of other recurrent genetic abnormalities in AML 3 (with the exception of rare cases in which both NPM1 and CEPBA mutations coexist); (3) AML with mutated NPM1 shows distinctive gene expression signatures 5,10,29 and microRNA profiles 6,7 ; (4) all NPM1 mutations generate common changes at the C terminus of nucleophosmin protein that appear to maximize nuclear export of NPM1 leukemic mutants, 1,[35][36][37] pointing to their cytoplasmic dislocation as the central event for leukemogenesis 36,38 ; (5) NPM1 mutations are stable during the course of the disease, [39][40][41] as the same type of NPM1 mutation is consistently detected at relapse in medullary and extramedullary sites. Loss of NPM1 mutation has been rarely observed in NPM1-mutated AML.…”

Section: Org Frommentioning

confidence: 99%

AML with mutated NPM1 carrying a normal or aberrant karyotype show overlapping biologic, pathologic, immunophenotypic, and prognostic features

Haferlach

Mecucci

Schnittger

et al. 2009

Blood

154

102

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Acute myeloid leukemia (AML) with mutated NPM1 usually carries normal karyotype (NK), but it may harbor chromosomal aberrations whose significance remains unclear. We addressed this question in 631 AML patients with mutated/ cytoplasmic NPM1. An abnormal karyotype (AK) was present in 93 of 631 cases (14.7%), the most frequent abnormalities being ؉8, ؉4, ؊Y, del(9q), ؉21. Chromosome aberrations in NPM1-mutated AML were similar to, but occurred less frequently than additional chromosome changes found in other AML with recurrent cytogenetic abnormalities according to WHO classification. Four of the 31 NPM1-mutated AML patients karyotyped at different time points had NK at diagnosis but AK at relapse: del(9q) (n ‫؍‬ 2), t(2;11) (n ‫؍‬ 1), inv(12) (n ‫؍‬ 1). NPM1-mutated AML with NK or AK showed overlapping morphologic, immunophenotypic (CD34 negativity), and gene expression profile (down-regulation of CD34 and up-regulation of HOX genes). No difference in survival was observed among NPM1-mutated AML patients independently of whether they carried a NK or an AK, the NPM1-mutated/FLT3-ITD negative cases showing the better prognosis. Findings in our patients point to chromosomal aberrations as secondary events, reinforce the concept that NPM1 mutation is a founder genetic lesion, and indicate that NPM1-mutated AML should be clinically handled as one entity, irrespective of the karyotype. (Blood. 2009;114: 3024-3032)

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“…[63][64][65] Accordingly, in patients with NPM1-mutated AML who were investigated by immunohistochemistry during the course of the disease, cytoplasmic nucleophosmin was consistently detected at relapse not only in the bone marrow but also in extramedullary sites. Persistence of NPM1 expression in leukaemic cell cytoplasm over a period of many years was demonstrated in patients at late relapse 66,67 and in a xenotransplant model of AML with mutated NPM1 in immunodeficient mice. 65 Moreover, the OCI-AML3 cell line, first established about 20 years ago, stably harbours NPM1 mutation A and displays aberrant nucleophosmin expression in cytoplasm.…”

Section: Npm Dislocation Into Cytoplasm: a Critical Event For Leukaemmentioning

confidence: 99%

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

et al. 2009

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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.

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Late relapse of acute myeloid leukemia with mutated NPM1 after eight years: evidence of NPM1 mutation stability

Cited by 29 publications

References 6 publications

A dose-dependent tug of war involving the NPM1 leukaemic mutant, nucleophosmin, and ARF

A dose-dependent tug of war involving the NPM1 leukaemic mutant, nucleophosmin, and ARF

AML with mutated NPM1 carrying a normal or aberrant karyotype show overlapping biologic, pathologic, immunophenotypic, and prognostic features

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

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