Clinical characteristics and prognostic implications of NPM1 mutations in acute myeloid leukemia

Suzuki, Tatsuya; Kiyoi, Hitoshi; Ozeki, Kazutaka; Tomita, Akihiro; Yamaji, Satomi; Suzuki, Ritsuro; Kodera, Yoshihisa; Miyawaki, Shuichi; Asou, Norio; Kuriyama, Kazutaka; Yagasaki, Fumiharu; Shimazaki, Chihiro; Akiyama, Hideki; Nishimura, Miki; Motoji, Toshiko; Shinagawa, Katsuji; Takeshita, Akira; Ueda, Ryuzo; Kinoshita, Tomohiro; Emi, Nobuhiko; Naoe, Tomoki

doi:10.1182/blood-2005-04-1733

Cited by 245 publications

(230 citation statements)

References 47 publications

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“…Several studies emphasize the high frequency of NPM1 mutations in middle-aged adults or more elderly individuals (average age, 58 years)33 and the rare incidence of mutations in individuals younger than 35 years 1033. In our data, the age pattern for NPM1 mutations in the Iranian context seems similar to that revealed by previous investigations.…”

Section: Discussionsupporting

confidence: 88%

“…In the study by Zhang et al,32 14.3% of AML patients with normal karyotype were reported to have a mutant NPM1. The other results were different: 24.9% in all AML cases,33 74.3% in normal-karyotype AMLs34 or 52.9% in normal-karyotype AMLs 10. In fact, in spite of relative differences in frequencies of these mutations, all studies imply a higher frequency of NPM1 mutations in AML cases with normal karyotype.…”

Section: Discussionmentioning

confidence: 77%

“…Thiede et al31 reported on NPM1 mutations mainly in M2, M5a and M5b, but not in the M3 subtype. No mutation was reported in the M3 subtype in the study by Suzuki et al33…”

Section: Discussionmentioning

confidence: 88%

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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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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 77%

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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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“…Several studies have observed FLT3 mutation status changes in small subsets of acute myeloid leukemia patients and have implied the prognostic importance. 10,16,[21][22][23][24][25][26][27][28][29] In aggregate, these data suggest that gain of FLT3 mutations may be associated with worse prognosis. 24,27,29,33 These patients also seem not to benefit from intensifying chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…10,16,[21][22][23][24][25][26][27][28][29] However, owing to a lack of a sufficient number of patients, no study has been able to provide statistical significant correlations between FLT3 status changes and disease progression. The goal of this study is to examine the clinical features and outcome of a large cohort of acute myeloid leukemia patients in whom FLT3 mutation status changed.…”

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confidence: 99%

Clinical impact of change of FLT3 mutation status in acute myeloid leukemia patients

et al. 2012

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FMS-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in acute myeloid leukemia and is associated with worse clinical outcome. Changes in FLT3 mutation status can occur during the course of disease, but the clinical impact of a change is unclear. We retrospectively reviewed 3555 acute myeloid leukemia patients, who have been assessed for FLT3 mutation at our institution between May 2002 and January 2011. We found that 42 (6.2%) out of 680 patients with FLT3 mutation experienced a change of FLT3 mutation status. In all, 36 patients with wild-type FLT3 at the time of initial diagnosis gained mutation (Negative/Positive) and six initially FLT3-mutated patients became wild type during their following relapses (Positive/Negative). The 5-year survival of these patients was similar to that of patients with persistently wild-type FLT3 (Negative/ Negative; P ¼ 0.464), and significantly better than patients who had stable FLT3 mutation during their disease course (Positive/Positive; Po0.001). However, after mutations became detectable in the Negative/Positive group, the forward survival of these patients tracked that of the Positive/Positive group after relapse (P ¼ 0.761). In addition, we did not find a significant difference in survival between patients with internal tandem duplications and those with point mutations in the tyrosine kinase domain of the FLT3 gene. These results suggest that FLT3 mutations are unstable and that there is potential clinical value in continuously monitoring FLT3 mutation status.

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Acute myeloid leukaemia

Smith¹,

McKerrell²

2016

The Genetic Basis of Haematological Cancers

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Clinical characteristics and prognostic implications of NPM1 mutations in acute myeloid leukemia

Cited by 245 publications

References 47 publications

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

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

Clinical impact of change of FLT3 mutation status in acute myeloid leukemia patients

Acute myeloid leukaemia

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