Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance

Verhaak, Roel G.W.; Goudswaard, Chantal; Putten, Wim van; Bijl, M; Sanders, Mathijs A.; Hugens, Wendy; Uitterlinden, André G.; Erpelinck, Claudia; Delwel, Ruud; Löwenberg, Bob; Valk, Peter J.M.

doi:10.1182/blood-2005-05-2168

Cited by 534 publications

(542 citation statements)

References 44 publications

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“…Interestingly, NPMc þ inversely correlates with NRAS mutations in AML patients (Verhaak et al, 2005). The observation that NPMc þ does not transform Arf À/À or p53 À/À MEFs is also in agreement with the notion that NPMc þ induces senescence through an Arf-independent mechanism.…”

Section: Discussionsupporting

confidence: 84%

The leukemia-associated cytoplasmic nucleophosmin mutant is an oncogene with paradoxical functions: Arf inactivation and induction of cellular senescence

et al. 2007

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Mutations leading to aberrant cytoplasmic localization of Nucleophosmin 1 (NPM1) have been recently identified as the most frequent genetic alteration in acute myelogenous leukemia. However, the oncogenic potential of this nucleophosmin mutant (NPMc +) has never been established, which casts doubt on its role in leukemogenesis. By performing classical transformation assays, we find that NPMc +, but not wild-type NPM, cooperates specifically with adenovirus E1A to transform primary mouse embryonic fibroblasts in soft agar. We demonstrate that NPMc + blocks the p19 Arf (Arf) induction elicited by E1A. Surprisingly, however, we find that NPMc + induces cellular senescence and that E1A is able to overcome this response. We propose a model whereby the NPMc + pro-senescence activity needs to be evaded for oncogenic transformation, even though NPMc + can concomitantly blunt the Arf/p53 pathway. These findings identify for the first time NPMc + as an oncogene and shed new unexpected light on its mechanism of action.

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Section: Discussionsupporting

confidence: 84%

The leukemia-associated cytoplasmic nucleophosmin mutant is an oncogene with paradoxical functions: Arf inactivation and induction of cellular senescence

et al. 2007

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“…In the study by Falini et al, the highest frequency was in M5b (87%), whereas the lowest was in M0 (13.6%). In the study by Verhaak et al,20 the emphasis was on the high rate of NPM1 mutations in M5 and M6 subtypes, and the lower frequency in other subtypes, including M3, but they did not report mutations in M0. In the study by Döhner et al,24 the highest frequency of NPM1 mutations was reported in M4 and M5.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, NPM1 binds to several proteins, like p53 and proteins that react to and regulate p53 (like Rb,17 p19ARF18 and HDM219). The high frequency of NPM1 mutations in normal-karyotype AMLs and the fact that cytoplasmic NPM1 fails to carry out its normal functions such as binding to proteins and transferring them lead to the hypothesis that mutations in NPM1 would be a primary event in leukemogenesis 20. Therefore, it seems that NPM1 mutations lead to acquiring additional genetic changes in AML leukemic cells 21.…”

mentioning

confidence: 99%

Detection of nucleophosmin and FMS-like tyrosine kinase-3 gene mutations in acute myeloid leukemia

Pazhakh

Zaker

Atashrazm

2011

Annals of Saudi Medicine

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BACKGROUND AND OBJECTIVES:Nucleophosmin gene mutations are frequently reported in acute myeloid leukemia (AML) patients with normal karyotype, which is also frequently associated with internal tandem duplication mutations in the FMS-like tyrosine kinase-3 gene. We sought to detect the nucleophosmin and FMS-like tyrosine kinase-3 (FLT3) internal tandem duplication (ITD) mutations among Iranian patients with AML and to assess the relationship between these mutations and the subtypes of the disease.DESIGN AND SETTING:Cross-sectional study of patients referred during 2007 through 2009.PATIENTS AND METHODS:Bone marrow and peripheral blood samples of 131 AML patients were randomly collected at the time of diagnosis and prior to treatment and the DNA extracted. After amplifying the nucleophosmin and FLT3 gene regions, positive cases were screened by conformation-sensitive gel electrophoresis and agarose gel electrophoresis techniques.RESULTS:Of 131 patients, 23 (17.5%) (0.95% CI=0.107-0.244) had nucleophosmin gene mutations. The highest frequency of such mutations was found among the subtypes of M4 (30.4%), M3 (21.7%) and M5 (17.4%). There was a high frequency of these mutations in the M3 subtype as well as a high frequency of allele D in all subtypes. Also, 21 (16.0%) samples (0.95% CI=0.092-0.229) had FLT3/ITD mutation, of which 8 samples had mutant nucleophosmin (8 of 23, 35%), and another 13 samples had wild-type nucleophosmin gene (13 of 108, 12%). There was a high degree of association between the occurrence of nucleophosmin and FLT3/ITD mutations (P=.012).CONCLUSION:Our data showed a high frequency of NPM1 mutations in the monocytic subtypes of AML, as well as a high degree of association between the occurrence of NPM1 and FLT3/ITD mutations.

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“…Approximately 50% of cytogenetically normal AML may carry a mutation in the nucleophosmin gene (NPM1) (25). The prognostic value of the presence of the NPM1 mutation appeared to depend on the additional presence of the internal tandem duplication (ITD) in the FLT3 tyrosine kinase receptor (FLT3/ITD) (26)(27)(28)(29). Myeloid leukemia's characterized by the NPM1 mutation but without FLT3/ITD, appeared to exhibit a more favorable prognosis with relapse rates less than 30%.…”

Section: Molecular Markersmentioning

confidence: 99%

The European LeukemiaNet AML Working Party consensus statement on allogeneic HSCT for patients with AML in remission: an integrated-risk adapted approach

et al. 2012

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Allogeneic hematopoietic stem cell transplantation (alloHSCT) is frequently applied as part of treatment in acute myeloid leukemia (AML) in first or subsequent remission. It reduces relapse, but non-relapse mortality (NRM) and morbidity may counterbalance that beneficial effect. Here we review recent studies reporting new disease specific prognostic markers as well as alloHSCT related risk factors to be identified at specific time points during treatment. We propose risk assessment as a dynamic process during treatment, incorporating both disease and transplant related factors for the decision to proceed either to alloHSCT or with a non transplant strategy, whereby alloHSCT may be favored if projected disease free survival can be expected to be improved by at least 10%, based on individual risk assessment. Pivotal for such an approach are initial disease risk assessment, search for a sibling or unrelated donor early after diagnosis, and the incorporation of time dependent risk factors, all within the context of an integrated therapeutic management approach.4

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Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance

Cited by 534 publications

References 44 publications

The leukemia-associated cytoplasmic nucleophosmin mutant is an oncogene with paradoxical functions: Arf inactivation and induction of cellular senescence

The leukemia-associated cytoplasmic nucleophosmin mutant is an oncogene with paradoxical functions: Arf inactivation and induction of cellular senescence

Detection of nucleophosmin and FMS-like tyrosine kinase-3 gene mutations in acute myeloid leukemia

The European LeukemiaNet AML Working Party consensus statement on allogeneic HSCT for patients with AML in remission: an integrated-risk adapted approach

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