Lack of nucleophosmin mutation in patients with myelodysplastic syndrome and acute myeloid leukemia with chromosome 5 abnormalities

Sekiguchi, Masayuki; Kitagawa, Yukiko; Wang, Yanhua; Yoshinaga, Kentaro; Kondo, Toshiaki; Kuroiwa, Hanae; Okada, Michiko; Mori, Naoki; Motoji, Toshiko

doi:10.1080/10428190701615900

Cited by 29 publications

(16 citation statements)

References 22 publications

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“…Our findings add to the body of evidence that the NPM1 mutation is a founder genetic lesion in NPMc + AML: i) cytoplasmic mutated nucleophosmin is specific for AML 1,30,31 and clinically shows close association with AML of de novo origin 1,[32][33][34] ; ii) all NPM1 mutations generate changes at the C-terminus of nucleophosmin protein which appear to maximise nuclear export of NPM leukemic mutants, 3,[35][36][37] pointing to cytoplasmic dislocation of the mutants as the central event for leukemogenesis; iii) NPM1 mutations are mutually exclusive with other recurrent genetic abnormalities, 1,38 with the exception of rare cases in which both NPM1 and CEPBA (or FLT3-ITD) mutations are found; 15 iv) they are stable during the course of the disease 39,40 as the same type of NPM1 mutation is consistently detected at relapse in medullary and extramedullary sites; 40 and v) quantitative real-time PCR shows that NPM1 mutations disappear at complete remission. 41,42 The major finding in the present study is that the onemutation mathematical model can explain the age specific incidence in NPMc + AML.…”

Section: Discussionmentioning

confidence: 76%

A one-mutation mathematical model can explain the age incidence of acute myeloid leukemia with mutated nucleophosmin (NPM1)

Liso¹,

Castiglione²,

Cappuccio³

et al. 2008

Haematologica

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Acute myeloid leukemia with mutated NPM1 gene and aberrant cytoplasmic expression of nucleophosmin (NPMc + acute myeloid leukemia) shows distinctive biological and clinical features. Experimental evidence of the oncogenic potential of the nucleophosmin mutant is, however, still lacking, and it is unclear whether other genetic lesion(s), e.g. FLT3 internal tandem duplication, cooperate with NPM1 mutations in acute myeloid leukemia development. An analysis of age-specific incidence, together with mathematical modeling of acute myeloid leukemia epidemiology, can help to uncover the number of genetic events needed to cause leukemia. We collected data on age at diagnosis of acute myeloid leukemia patients from five European Centers in Germany, The Netherlands and Italy, and determined the age-specific incidence of AML with mutated NPM1 (a total of 1,444 cases) for each country. Linear regression of the curves representing age-specific rates of diagnosis per year showed similar slopes of about 4 on a double logarithmic scale. We then adapted a previously designed mathematical model of hematopoietic tumorigenesis to analyze the age incidence of acute myeloid leukemia with mutated NPM1 and found that a one-mutation model can explain the incidence curve of this leukemia entity. This model fits with the hypothesis that NPMc + acute myeloid leukemia arises from an NPM1 mutation with haploinsufficiency of the wild-type NPM1 allele.Key words: acute myeloid leukemia, nucleophosmin, mutation.

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Section: Discussionmentioning

confidence: 76%

A one-mutation mathematical model can explain the age incidence of acute myeloid leukemia with mutated nucleophosmin (NPM1)

Liso¹,

Castiglione²,

Cappuccio³

et al. 2008

Haematologica

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“…[5][6][7][8]10 Thus, the difference in frequency of NPM1 mutations between therapy-related and de novo AML seems to rely mainly on a difference in cytogenetic characteristics, with a normal Table 1 Nucleotide and theoretical peptide sequences of the NPM1 exon 12 translated region 4 The occurrence of NPM1 mutations in de novo MDS is uncommon and controversial. 30,31 Our observation of three cases of NPM1 mutations in patients with t-MDS is therefore surprising. All three cases, however, were atypical.…”

Section: Discussionmentioning

confidence: 92%

NPM1 mutations in therapy-related acute myeloid leukemia with uncharacteristic features

2008

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Frameshift mutations of the nucleophosmin gene (NPM1) were recently reported as a frequently occurring abnormality in patients with de novo acute myeloid leukemia (AML). To evaluate the frequency of NPM1 mutations in patients with therapy-related myelodysplasia (t-MDS) and therapy-related AML (t-AML), and their possible association to type of previous therapy and to other gene mutations, 140 patients with t-MDS or t-AML were analyzed for mutations of NPM1. NPM1 mutations were observed in 7 of 51 patients presenting as overt t-AML, as compared to only 3 of 89 patients presenting as t-MDS (P ¼ 0.037). The mutations were not related to any specific type of previous therapy, but they were significantly associated with a normal karyotype and mutations of FLT3 (P ¼ 0.0002 for both comparisons). Only 1 of 10 patients with NPM1 mutations presented chromosome aberrations characteristic of therapyrelated disease, and 7qÀ/À7, the most frequent abnormalities of t-MDS/t-AML, were not observed (P ¼ 0.002). This raises the question whether some of the cases presenting NPM1 mutations were in fact cases of de novo leukemia. The close association to class I mutations and the inverse association to class II mutations suggest mutations of NPM1 as representing a class II mutation-like abnormality in AML. Leukemia (2008) 22, 951-955;

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“…26 Although NPM1 and FLT3 mutations are two of the most common molecular abnormalities in acute myeloid leukemia, particularly within the cytogenetically normal group, they are relatively uncommon in myeloproliferative neoplasms and myelodysplastic syndromes. 14,[28][29][30] Studies that evaluated chronic myelomonocytic leukemia specifically found the NPM1 mutation in 5-13% Transformed chronic myelomonocytic leukemia of patients. 14 In one study, all three NPM1-mutated chronic myelomonocytic leukemia patients had rapid progression to overt acute myeloid leukemia, whereas in the other study, one of the two patients progressed to acute myeloid leukemia.…”

Section: Discussionmentioning

confidence: 99%

Clinicopathologic analysis of acute myeloid leukemia arising from chronic myelomonocytic leukemia

Courville

Kourda

et al. 2013

Modern Pathology

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Acute myeloid leukemia arising from chronic myelomonocytic leukemia is currently classified as acute myeloid leukemia with myelodysplasia-related changes, a high-risk subtype. However, the specific features of these cases have not been well described. We studied 38 patients with chronic myelomonocytic leukemia who progressed to acute myeloid leukemia. We compared the clinicopathologic and genetic features of these cases with 180 patients with de novo acute myeloid leukemia and 34 patients with acute myeloid leukemia following myelodysplastic syndromes. We also examined features associated with progression from chronic myelomonocytic leukemia to acute myeloid leukemia by comparing the progressed chronic myelomonocytic leukemia cases with a cohort of chronic myelomonocytic leukemia cases that did not transform to acute myeloid leukemia. Higher white blood cell count, marrow cellularity, karyotype risk score, and Revised International Prognostic Scoring System score were associated with more rapid progression from chronic myelomonocytic leukemia to acute myeloid leukemia. Patients with acute myeloid leukemia ex chronic myelomonocytic leukemia were older (Po0.01) and less likely to receive aggressive treatment (P ¼ 0.02) than de novo acute myeloid leukemia patients. Most cases showed monocytic differentiation and fell into the intermediate acute myeloid leukemia karyotype risk group; 55% had normal karyotype and 17% had NPM1 mutation. Median overall survival was 6 months, which was inferior to de novo acute myeloid leukemia (17 months, P ¼ 0.002) but similar to post myelodysplastic syndrome acute myeloid leukemia. On multivariate analysis of all acute myeloid leukemia patients, only age and karyotype were independent prognostic variables for overall survival. Our findings indicate that acute myeloid leukemia following chronic myelomonocytic leukemia displays aggressive behavior and support placement of these cases within the category of acute myeloid leukemia with myelodysplasia-related changes. The poor prognosis of these patients may be related to an older population and lack of favorable-prognosis karyotypes that characterize many de novo acute myeloid leukemia cases.

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Lack of nucleophosmin mutation in patients with myelodysplastic syndrome and acute myeloid leukemia with chromosome 5 abnormalities

Cited by 29 publications

References 22 publications

A one-mutation mathematical model can explain the age incidence of acute myeloid leukemia with mutated nucleophosmin (NPM1)

A one-mutation mathematical model can explain the age incidence of acute myeloid leukemia with mutated nucleophosmin (NPM1)

NPM1 mutations in therapy-related acute myeloid leukemia with uncharacteristic features

Clinicopathologic analysis of acute myeloid leukemia arising from chronic myelomonocytic leukemia

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