NPM1-Mutated Myeloid Neoplasms with &lt;20% Blasts: A Really Distinct Clinico-Pathologic Entity?

Forghieri, Fabio; Nasillo, Vincenzo; Paolini, Ambra; Bettelli, Francesca; Pioli, Valeria; Giusti, Davide; Gilioli, Andrea; Colasante, Corrado; Acquaviva, Gloria; Riva, Giovanni; Barozzi, Patrizia; Maffei, Rossana; Potenza, Leonardo; Marasca, Roberto; Fozza, Claudio; Tagliafico, Enrico; Trenti, Tommaso; Comoli, Patrizia; Longo, Giuseppe; Luppi, Mario

doi:10.3390/ijms21238975

Cited by 30 publications

(22 citation statements)

References 124 publications

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“…NPM1 mutations are recurrent molecular lesions, occurring in nearly 30% of AML patients, are stable across the disease course and are considered to be driver events, highly specific for leukemogenesis [5,[7][8][9][10]. Indeed, NPM1-mutated C-terminal aminoacidic sequences are not found in either malignancies different from AML or normal tissues, resulting in leukemiaspecific neoantigens considered optimal target for immunotherapy [2,3,15,16,19,20,88,89].…”

Section: Discussionmentioning

confidence: 99%

“…Relevant to this, nucleophosmin (NPM1) gene mutations, observed in nearly 30% of adult AML patients, accounting for approximately 50-60% of cases among the cytogenetically normal AML subgroup, represent one of the most frequent genetic lesions documented in AML [5][6][7][8]. Moreover, NPM1 mutations are highly specific, being almost exclusively found in AML, and generally expressed in the entire leukemic population, while not detectable in clonal hematopoiesis [5,[7][8][9][10]. As expected for driver genetic lesions, NPM1 mutations are also stable throughout the course of the disease, with most relapses being due to the recurrence of the original NPM1-mutated clone, whereas only 5% to 10% of recurrent cases are characterized by the absence of NPM1 mutations.…”

Section: Introductionmentioning

confidence: 99%

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Neoantigen-Specific T-Cell Immune Responses: The Paradigm of NPM1-Mutated Acute Myeloid Leukemia

Forghieri

Riva

Lagreca

et al. 2021

IJMS

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The C-terminal aminoacidic sequence from NPM1-mutated protein, absent in normal human tissues, may serve as a leukemia-specific antigen and can be considered an ideal target for NPM1-mutated acute myeloid leukemia (AML) immunotherapy. Different in silico instruments and in vitro/ex vivo immunological platforms have identified the most immunogenic epitopes from NPM1-mutated protein. Spontaneous development of endogenous NPM1-mutated-specific cytotoxic T cells has been observed in patients, potentially contributing to remission maintenance and prolonged survival. Genetically engineered T cells, namely CAR-T or TCR-transduced T cells, directed against NPM1-mutated peptides bound to HLA could prospectively represent a promising therapeutic approach. Although either adoptive or vaccine-based immunotherapies are unlikely to be highly effective in patients with full-blown leukemia, these strategies, potentially in combination with immune-checkpoint inhibitors, could be promising in maintaining remission or preemptively eradicating persistent measurable residual disease, mainly in patients ineligible for allogeneic hematopoietic stem cell transplant (HSCT). Alternatively, neoantigen-specific donor lymphocyte infusion derived from healthy donors and targeting NPM1-mutated protein to selectively elicit graft-versus-leukemia effect may represent an attractive option in subjects experiencing post-HSCT relapse. Future studies are warranted to further investigate dynamics of NPM1-mutated-specific immunity and explore whether novel individualized immunotherapies may have potential clinical utility in NPM1-mutated AML patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Neoantigen-Specific T-Cell Immune Responses: The Paradigm of NPM1-Mutated Acute Myeloid Leukemia

Forghieri

Riva

Lagreca

et al. 2021

IJMS

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“…The serial acquirement of somatic mutations in myeloid clone(s) was described as the multistep pathogenesis of AML. Several lines of evidence prove that NPM1 mutations are responsible for the definitive acute leukemic transformation, therefore considered as leukemia founder mutations: (i) NPM1 mutations are completely absent in the population without hematological malignancies even at a higher age [ 22 – 24 ]; (ii) NPM1 mutations cannot be detected in AML patients months or years before the manifestation of AML [ 25 , 26 ]; (iii) NPM1 mutations occur rather rarely (approximately 2–3%) in preleukemic myeloid malignancies such as myelodysplastic syndrome (MDS) or in myelodysplastic/myeloproliferative neoplasm (MDS/MPN), which are mainly characterized by the progression to overt AML [ 27 ]; (iv) NPM1 mutations were not present in preleukemic hematopoietic stem cells [ 28 , 29 ]. Our observation that NPM1 VAF decreased below 2.5% in all cases with morphologic leukemia-free state, also proved that NPM1 mutations do not occur in the preleukemic state.…”

Section: Discussionmentioning

confidence: 99%

Nucleophosmin1 and isocitrate dehydrogenase 1 and 2 as measurable residual disease markers in acute myeloid leukemia

et al. 2021

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Monitoring measurable residual disease (MRD) in acute myeloid leukemia (AML) plays an important role in predicting relapse and outcome. The applicability of the leukemia-initiating nucleophosmin1 (NPM1) gene mutations in MRD detection is well-established, while that of isocitrate dehydrogenase1/2 (IDH1/2) mutations are matter of debate. The aim of this study was to investigate the stability of NPM1 and IDH1/2 mutations at diagnosis and relapse retrospectively in 916 adult AML patients. The prognostic value of MRD was evaluated by droplet digital PCR on the DNA level in a selected subgroup of patients in remission. NPM1 re-emerged at relapse in 91% (72/79), while IDH1/2 in 87% (20/23) of mutation-positive cases at diagnosis. NPM1 mutation did not develop at relapse, on the contrary novel IDH1/2 mutations occurred in 3% (3/93) of previously mutation-negative cases. NPM1 MRD-positivity after induction (n = 116) proved to be an independent, adverse risk factor (MRDpos 24-month OS: 39.3±6.2% versus MRDneg: 58.5±7.5%, p = 0.029; HR: 2.16; 95%CI: 1.25–3.74, p = 0.006). In the favorable subgroup of mutated NPM1 without fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) or with low allelic ratio, NPM1 MRD provides a valuable prognostic biomarker (NPM1 MRDpos versus MRDneg 24-month OS: 42.9±6.7% versus 66.7±8.6%; p = 0.01). IDH1/2 MRD-positivity after induction (n = 62) was also associated with poor survival (MRDpos 24-month OS: 41.3±9.2% versus MRDneg: 62.5±9.0%, p = 0.003; HR 2.81 95%CI 1.09–7.23, p = 0.032). While NPM1 variant allele frequency decreased below 2.5% in remission in all patients, IDH1/2 mutations (typically IDH2 R140Q) persisted in 24% of cases. Our results support that NPM1 MRD even at DNA level is a reliable prognostic factor, while IDH1/2 mutations may represent pre-leukemic, founder or subclonal drivers.

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“…These studies also pointed out that the NPM1 mutation was proposed as a secondary event in the conversion of CMML to AML (Courville et al, 2013;Lin and Falini, 2015). Some researchers have suggested that wild-type or mutated NPM1 may be a diagnostic basis for AML, irrespective of bone marrow blast percentage (Forghieri et al, 2020). The study by Xu J et al showed DNMT3A (Arg882) drives CMML through changing gene expression and DNA methylation in hematopoietic cells (Xu et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

The Clinical Features and Prognosis of NPM1/FLT3-ITD/DNMT3A Triple-mutated Acute Myeloid Leukaemia

Luo¹,

Liu²,

Liang³

et al. 2021

Preprint

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Purpose: Previous studies have shown that patients with NPM1+/FLT3-ITD+ acute myeloid leukaemia (AML) have a poor prognosis, especially those with a high FLT3-ITD allelic ratio. However, no studies have confirmed a clear prognostic impact of DNMT3A on NPM1+/FLT3-ITD+ AML patients. Methods: Our study included a total of 165 patients with newly diagnosed non-acute promyelocytic leukaemia (non-APL) AML at The First Hospital of Lanzhou University between January 2018 and June 2021. Further bioinformatics analysis was performed using the Gene Expression Omnibus (GEO) database. Results: We retrospectively studied 165 patients newly diagnosed non-APL AML and identified 11 (6.7%) patients with NPM1/FLT3-ITD/DNMT3A triple mutations. The patients with triple-mutated AML had advanced age, higher white blood cell (WBC) counts, de novo AML, normal karyotypes, and poor survival, and all were in the M4/M5 French-American-British (FAB) category. Notably, half of the patients with triple-mutated AML had mature monocyte characteristics that were difficult to distinguish from chronic myelomonocytic leukaemia (CMML). We validated the prognosis of patients with triple-mutated AML by further bioinformatics analysis and found that the GNG4 gene, one of the hub genes, was related to triple-mutated AML patients' survival. Conclusion: Our data demonstrate that DNMT3A gene mutation has adverse prognostic significance in NPM1+FLT3-ITD+comutation AML patients.

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NPM1-Mutated Myeloid Neoplasms with <20% Blasts: A Really Distinct Clinico-Pathologic Entity?

Cited by 30 publications

References 124 publications

Neoantigen-Specific T-Cell Immune Responses: The Paradigm of NPM1-Mutated Acute Myeloid Leukemia

Neoantigen-Specific T-Cell Immune Responses: The Paradigm of NPM1-Mutated Acute Myeloid Leukemia

Nucleophosmin1 and isocitrate dehydrogenase 1 and 2 as measurable residual disease markers in acute myeloid leukemia

The Clinical Features and Prognosis of NPM1/FLT3-ITD/DNMT3A Triple-mutated Acute Myeloid Leukaemia

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