NPM1 mutations and cytoplasmic nucleophosmin are mutually exclusive of recurrent genetic abnormalities: a comparative analysis of 2562 patients with acute myeloid leukemia

Falini, Brunangelo; Mecucci, Cristina; Saglio, Giuseppe; Coco, Francesco Lo; Diverio, Daniela; Brown, Patrick; Pane, Fabrizio; Mancini, Marco; Martelli, Maria Paola; Pileri, Stefano; Haferlach, Torsten; Haferlach, Claudia; Schnittger, Susanne

doi:10.3324/haematol.12153

Cited by 70 publications

(48 citation statements)

References 21 publications

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“…377 Those mutations are most frequent in NK-AML (45%-60%), [377][378][379] and occur only rarely in association with the recurrent cytogenetic abnormalities that define CBF-AML-AML with t(8;21) or inv(16)/t(16;16)-or APL. 377,378,380,381 This was supported by 2 studies from our SR, for both adult (Gaidzik et al 100 reported P , .05 incidence of NPM1 mutations compared with other AML subtypes) and pediatric patients (Pollard et al 339 reported 0% incidence of NPM1 and CEBPA mutations). Cytogenetic abnormalities associated with NPM1 mutations are most frequently single genetic abnormalities (ie, þ8, þ4, ÀY, del(9q), þ21) 378,382 and are only rarely associated with a complex karyotype (P , .001).…”

supporting

confidence: 69%

Initial Diagnostic Workup of Acute Leukemia: Guideline From the College of American Pathologists and the American Society of Hematology

Arber¹,

Borowitz²,

Cessna³

et al. 2017

Archives of Pathology &Amp; Laboratory Medicine

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Context.-A complete diagnosis of acute leukemia requires knowledge of clinical information combined with morphologic evaluation, immunophenotyping and karyotype analysis, and often, molecular genetic testing. Although many aspects of the workup for acute leukemia are well accepted, few guidelines have addressed the different aspects of the diagnostic evaluation of samples from patients suspected to have acute leukemia.Objective.-To develop a guideline for treating physicians and pathologists involved in the diagnostic and prognostic evaluation of new acute leukemia samples, including acute lymphoblastic leukemia, acute myeloid leukemia, and acute leukemias of ambiguous lineage.Design.-The College of American Pathologists and the American Society of Hematology convened a panel of experts in hematology and hematopathology to develop recommendations. A systematic evidence review was conducted to address 6 key questions. Recommendations were derived from strength of evidence, feedback received during the public comment period, and expert panel consensus.Results.-Twenty-seven guideline statements were established, which ranged from recommendations on what clinical and laboratory information should be available as part of the diagnostic and prognostic evaluation of acute leukemia samples to what types of testing should be performed routinely, with recommendations on where such testing should be performed and how the results should be reported.Conclusions.-The guideline provides a framework for the multiple steps, including laboratory testing, in the evaluation of acute leukemia samples. Some aspects of the guideline, especially molecular genetic testing in acute leukemia, are rapidly changing with new supportive literature, which will require on-going updates for the guideline to remain relevant.

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supporting

confidence: 69%

Initial Diagnostic Workup of Acute Leukemia: Guideline From the College of American Pathologists and the American Society of Hematology

Arber¹,

Borowitz²,

Cessna³

et al. 2017

Archives of Pathology &Amp; Laboratory Medicine

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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: 99%

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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“…Among the most compelling evidence that AML with mutated NPM1 represents an entity is that NPM1 mutation -or its immunohistochemical surrogate, cytoplasmic nucleophosmin 5 -is specific for AML 6 (usually of de novo origin), is very stable during the course of the disease, 7 is mutually exclusive of AML carrying recurrent genetic abnormalities 8 and associates with distinct gene expression 9 and microRNA profiles. 10 However, no investigation has, as yet, been carried out into the relationship between NPMc + AML and the blastic plasmacytoid dendritic cell (BPDC) neoplasm 11 (previously known as blastic NK-cell lymphoma or agranular CD4 + /CD56 + hematodermic neoplasm), that has been also introduced as a distinct entity in the new WHO classification.…”

Section: Introductionmentioning

confidence: 99%

Cytoplasmic nucleophosmin is not detected in blastic plasmacytoid dendritic cell neoplasm

Facchetti¹,

Pileri²,

Agostinelli³

et al. 2008

Haematologica

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the presence of NPM1 mutations) but nucleus-restricted in BPDC neoplasm (because of a germline NPM1 gene). Our results, have important diagnostic implications, further clarify the cell of origin of NPMc + AML, and justify the inclusion of AML with mutated NPM1 and BPDC neoplasm as separate entities in the new WHO classification. Design and Methods Pathological samplesThe aim of this study was to investigate the presence of NPM1 mutations in a wide spectrum of PDC proliferations. The following pathological samples were studied: n=13 typical BPDC neoplasms, whose phenotypic features are summarized in Table 1; reactive lymph nodes (n=16), myelodysplastic syndromes (n=14), AML (n=9) and myeloid sarcoma (n=5) harboring nodules of mature PDCs. Since no fresh material for molecular analysis was available from these cases, we used immunohistochemistry to detect aberrant cytoplasmic expression of nucleophosmin that is known to be fully predictive of NPM1 mutations. 5 Immunohistochemical studiesParaffin sections from all pathological samples were subjected to antigen retrieval and stained with antibodies directed against fixative-resistant epitopes of the protein nucleophosmin 1 and various PDC-associated markers. Nucleophosmin was detected using the monoclonal antibody (mAb) anti-NPM (clone 376) 1 ; PDCs were identified using mAbs anti-CD4 (clone OPD4; DakoCytomation), anti-CD56 (clone 1B6; NovoCastra), anti-CD123 (clone 7G3; BD Pharmingen), anti-TCL1 (clone TCL1A; Upstate), and anti-CLA (clone HECA-452; BD Pharmingen). Four cases were immunostained with an antibody directed against the new PDC marker CD2AP (kindly provided by Dr. Teresa Marafioti, University of Oxford). All samples were also investigated for expression of C23/nucleolin (mAb anti-C23, clone MS-3; Santa Cruz Biotechnology), the CD34 (mAb antibody anti-CD34, clone Qbend/10; DakoCytomation) and CD68 macrophage-restricted molecule (mAb PG-M1 generated in B. Falini's laboratory).The antibody-antigen reaction was revealed by immunoalkaline phosphatase (APAAP) or immunoperoxidase, according to standard procedures. 1 Results and DiscussionAll 13 BPDC neoplasms expressed three or more of the PDC-associated molecules CD4, CD56, CLA, CD123, TCL1 (Table 1; Figures 1 and 2), including the recently described PDC marker CD2AP 12 that was investigated in 4 cases (data not shown); all 10 samples investigated were CD34-negative (Table 1). Notably, tumor cells from all specimens showed nucleus-restricted expression of nucleophosmin (Figures 1 and 2) that was the same as C23/nucleolin and was fully predictive of NPM1 gene in a germline configuration. Interestingly, the nucleusrestricted positivity for nucleophosmin was also observed in paraffin sections from bone marrow biopsies of 14 patients with leukemias of ambiguous lineage (Online Supplementary Figure 1S) as defined by WHO, i.e. pathological conditions which share some but not all immunophenotypic features of BPDC neoplasm.11 The nucleophosmin staining pattern in BPDC neoplasm and leukemias of ambiguous lineages clear...

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NPM1 mutations and cytoplasmic nucleophosmin are mutually exclusive of recurrent genetic abnormalities: a comparative analysis of 2562 patients with acute myeloid leukemia

Cited by 70 publications

References 21 publications

Initial Diagnostic Workup of Acute Leukemia: Guideline From the College of American Pathologists and the American Society of Hematology

Initial Diagnostic Workup of Acute Leukemia: Guideline From the College of American Pathologists and the American Society of Hematology

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

Cytoplasmic nucleophosmin is not detected in blastic plasmacytoid dendritic cell neoplasm

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