Cytoplasmic Nucleophosmin in Acute Myelogenous Leukemia with a Normal Karyotype

Falini, Brunangelo; Mecucci, Christina; Tiacci, Enrico; Alcalay, Myriam; Rosati, Roberto; Pasqualucci, Laura; Starza, Roberta La; Diverio, Daniela; Colombo, Emanuela; Santucci, A; Bigerna, Barbara; Pacini, Roberta; Pucciarini, Alessandra; Liso, Arcangelo; Vignetti, Marco; Fazi, Paola; Meani, Natalia; Pettirossi, Valentina; Saglio, Giuseppe; Mandelli, Franco; Lo‐Coco, Francesco; Pelicci, PierGiuseppe; Martelli, Massimo F.

doi:10.1056/nejmoa041974

Cited by 1,672 publications

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“…In the study by Falini et al,11 38% of AML patients had normal karyotype, among whom 61.7% had NPM1 mutations. The total frequency of NPM1 mutations among all AML cases in this study was reported to be 35.2%.…”

Section: Discussionmentioning

confidence: 89%

“…Different methods have been described so far to screen and assess NPM1 mutations. These include use of monoclonal antibodies and immunohistochemistry,11 denaturing high-performance liquid chromatography (DHPLC),27 capillary electrophoresis of multiplex PCR products,28 and also fluorescence resonance energy transfer (FRET) 29. In our study, the conformation-sensitive gel electrophoresis (CSGE) technique was used to screen AML patients with NPM1 mutations.…”

Section: Discussionmentioning

confidence: 99%

“…However, on the basis of previous reports on the higher frequency of cytogenetic abnormalities among Iranian AML patients,35 it can be said that it is not unlikely that the above-stated fact has accounted for the lower frequency of NPM1 mutations in our results. Falini et al11 reported NPM1 mutations in AML subtypes based on FAB classification in all subtypes except M3, M4Eo and M7. In the study by Falini et al, the highest frequency was in M5b (87%), whereas the lowest was in M0 (13.6%).…”

Section: Discussionmentioning

confidence: 99%

“…Diagnoses were done through morphologic, cytochemical and immunophenotypic assessments by flow cytometry and the patients classified according to FAB criteria. To screen the NPM1 mutations, polymerase chain reaction (PCR) amplification of NPM1 exon 12 was carried out using primers NPM1-F (5’-TTAACTCTCTGGTGGTAGAATGAA-3’) and NPM1-R (5’-CAAGACTATTTGCCATTCCTAAC-3’), as described in previous studies 11. The total reaction volume of 50 μL contained approximately 100 ng DNA, 10 pmol of each primer, deoxynucleoside triphosphates (dNTPs, 10 mM each), 2.5 U Prime Taq polymerase and reaction buffer (GENET BIO, Korea) and ddH 2 O.…”

Section: Methodsmentioning

confidence: 99%

“…Therefore, it seems that NPM1 mutations lead to acquiring additional genetic changes in AML leukemic cells 21. Moreover, NPM1 mutations often occur in association with FLT3/ITD mutations 11. FLT3 is a receptor tyrosine kinase with important roles in hematopoietic stem/progenitor cell survival and proliferation 22…”

mentioning

confidence: 99%

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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: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

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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Contemporary Management of Acute Myeloid Leukemia

Venugopal,

Sekeres

2024

JAMA Oncol

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ImportanceAcute myeloid leukemia (AML) is a clonal hematopoietic cancer that disrupts normal hematopoiesis, ultimately leading to bone marrow failure and death. The annual incidence rate of AML is 4.1 per 100 000 people in the US and is higher in patients older than 65 years. Acute myeloid leukemia includes numerous subgroups with heterogeneous molecular profiles, treatment response, and prognosis. This review discusses the evidence supporting frontline therapies in AML, the major principles that guide therapy, and progress with molecularly targeted therapy.ObservationsAcute myeloid leukemia is a genetically complex, dynamic disease. The most commonly altered genes include FLT3, NPM1, DNMT3A, IDH1, IDH2, TET2, RUNX1, NRAS, and TP53. The incidence of these alterations varies by patient age, history of antecedent hematologic cancer, and previous exposure to chemotherapy and/or radiotherapy for any cancer. Since 2010, molecular data have been incorporated into AML prognostication, gradually leading to incorporation of targeted therapies into the initial treatment approach of induction chemotherapy and subsequent management. The first molecularly targeted inhibitor, midostaurin, was approved to treat patients with AML with FLT3 variants in 2017. Since then, the understanding of the molecular pathogenesis of AML has expanded, allowing the identification of additional potential targets for drug therapy, treatment incorporation of molecularly targeted therapies (midostaurin, gilteritinib, and quizartinib targeting FLT3 variants; ivosidenib and olutasidenib targeting IDH1 variants, and enasidenib targeting IDH2), and identification of rational combination regimens. The approval of hypomethylating agents combined with venetoclax has revolutionized the therapy of AML in older adults, extending survival over monotherapy. Additionally, patients are now referred for hematopoietic cell transplant on a more rational basis.Conclusions and RelevanceIn the era of genomic medicine, AML treatment is customized to the patient’s comorbidities and AML genomic profile.

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Selective regulation of type II interferon‐inducible genes by NPM1/nucleophosmin

et al. 2018

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Nucleophosmin (NPM1) is a multifunctional nucleolar protein. Here, we analyze the role of NPM1 in gene expression using our previous microarray data and find a relationship between NPM1 and interferon (IFN)-γ-inducible genes. We show that NPM1 selectively regulates the expression of a subset of IFN-γ-inducible genes and directly binds to two important transcription factors in the type II IFN pathway: signal transducer and activator of transcription 1 and interferon regulatory factor 1 (IRF1). Furthermore, NPM1 is found to regulate the IFN-γ-inducible promoter activity of major histocompatibility complex class II transactivator (CIITA), and mutation of the IRF1-binding site on the CIITA promoter abolishes the effect of NPM1. Our results suggest a novel mechanism for IFN-γ-mediated gene expression by NPM1.

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Cytoplasmic Nucleophosmin in Acute Myelogenous Leukemia with a Normal Karyotype

Cited by 1,672 publications

References 35 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

Contemporary Management of Acute Myeloid Leukemia

Selective regulation of type II interferon‐inducible genes by NPM1/nucleophosmin

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