NPM1 mutations may reveal acute myeloid leukemia in cases otherwise morphologically diagnosed as myelodysplastic syndromes or myelodysplastic/myeloproliferative neoplasms

Forghieri, Fabio; Paolini, Ambra; Morselli, Monica; Bigliardi, Sara; Bonacorsi, Goretta; Leonardi, Giovanna; Coluccio, Valeria; Maccaferri, Monica; Fantuzzi, Valeria; Faglioni, Laura; Colaci, Elisabetta; Soci, Francesco; Nasillo, Vincenzo; Messerotti, Andrea; Arletti, Laura; Pioli, Valeria; Zucchini, Patrizia; Quadrelli, Chiara; Corradini, Giorgia; Giacobbi, Francesca; Vallerini, Daniela; Riva, Giovanni; Barozzi, Patrizia; Lagreca, Ivana; Marasca, Roberto; Narni, Franco; Mecucci, Cristina; Ottaviani, Emanuela; Martinelli, Giovanni; Falini, Brunangelo; Luppi, Mario; Potenza, Leonardo

doi:10.3109/10428194.2015.1026900

Cited by 25 publications

(50 citation statements)

References 18 publications

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“…As expected for founder genetic lesions, NPM1 mutations are specific, being almost exclusively restricted to AML, usually de novo, and generally expressed in the whole leukemic population [ 13 , 14 , 20 ]. Notably, NPM1 -mutated AML, showing distinctive genetic, pathologic, immunophenotypic and clinical features, has now been recognized as a full distinct entity among AML with recurrent genetic abnormalities in the 2016 revision of World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia [ 21 ].…”

Section: Npm1 Mutations In Aml: Biological and mentioning

confidence: 99%

“…High NPM1 -mutated allele burden at diagnosis was an independent predictor of unfavorable clinical outcomes, particularly in patients who received HSCT in first CR and in the subgroup of subjects with concomitant DNMT3A mutations. Because of BM multilineage involvement of NPM1 mutations not being restricted to cells with blast morphology [ 12 , 16 , 20 ], the VAF could in fact reveal the true clonal disease burden. Higher NPM1 mutant allele burden may be less amenable to eradication by intensive chemotherapy, potentially resulting in a higher likelihood of MRD persistence.…”

Section: Npm1 Mutation Levels At Aml Diagnosismentioning

confidence: 99%

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Minimal/Measurable Residual Disease Monitoring in NPM1-Mutated Acute Myeloid Leukemia: A Clinical Viewpoint and Perspectives

Forghieri

Comoli

Marasca

et al. 2018

IJMS

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Acute myeloid leukemia (AML) with NPM1 gene mutations is currently recognized as a distinct entity, due to its unique biological and clinical features. We summarize here the results of published studies investigating the clinical application of minimal/measurable residual disease (MRD) in patients with NPM1-mutated AML, receiving either intensive chemotherapy or hematopoietic stem cell transplantation. Several clinical trials have so far demonstrated a significant independent prognostic impact of molecular MRD monitoring in NPM1-mutated AML and, accordingly, the Consensus Document from the European Leukemia Net MRD Working Party has recently recommended that NPM1-mutated AML patients have MRD assessment at informative clinical timepoints during treatment and follow-up. However, several controversies remain, mainly with regard to the most clinically significant timepoints and the MRD thresholds to be considered, but also with respect to the optimal source to be analyzed, namely bone marrow or peripheral blood samples, and the correlation of MRD with other known prognostic indicators. Moreover, we discuss potential advantages, as well as drawbacks, of newer molecular technologies such as digital droplet PCR and next-generation sequencing in comparison to conventional RQ-PCR to quantify NPM1-mutated MRD. In conclusion, further prospective clinical trials are warranted to standardize MRD monitoring strategies and to optimize MRD-guided therapeutic interventions in NPM1-mutated AML patients.

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Section: Npm1 Mutations In Aml: Biological and mentioning

confidence: 99%

Section: Npm1 Mutation Levels At Aml Diagnosismentioning

confidence: 99%

Minimal/Measurable Residual Disease Monitoring in NPM1-Mutated Acute Myeloid Leukemia: A Clinical Viewpoint and Perspectives

Forghieri

Comoli

Marasca

et al. 2018

IJMS

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“…Nucleophosmin ( NPM1 ) gene mutations, occurring in approximately 30% of adult acute myeloid leukemia (AML) cases, and in 50–60% of AML cases with a normal karyotype, represent one of the most frequent molecular lesions observed in AML [1–3]. Moreover, NPM1 mutations are specific, being almost exclusively restricted to AML, and usually expressed in the entire leukemic population [1, 4, 5]. As expected for founder genetic lesions, they are also stable throughout the course of the disease, with NPM1 mutations almost invariably documented in patients experiencing AML relapse [4] Most importantly, NPM1 mutations result in structural changes of the C-terminus of the NPM1 protein, with subsequent aberrant cytoplasmic delocalization, leading to perturbations in multiple cellular pathways, critical for leukemogenesis [1, 4].…”

Section: Introductionmentioning

confidence: 99%

Characterization and dynamics of specific T cells against nucleophosmin-1 (NPM1)-mutated peptides in patients with NPM1-mutated acute myeloid leukemia

et al. 2019

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Nucleophosmin(NPM1)-mutated protein, a leukemia-specific antigen, represents an ideal target for AML immunotherapy. We investigated the dynamics of NPM1-mutated-specific T cells on PB and BM samples, collected from 31 adult NPM1-mutated AML patients throughout the disease course, and stimulated with mixtures of 18 short and long peptides (9-18mers), deriving from the complete C-terminal of the NPM1-mutated protein. Two 9-mer peptides, namely LAVEEVSLR and AVEEVSLRK (13.9–14.9), were identified as the most immunogenic epitopes. IFNγ-producing NPM1-mutated-specific T cells were observed by ELISPOT assay after stimulation with peptides 13.9–14.9 in 43/85 (50.6%) PB and 34/80 (42.5%) BM samples. An inverse correlation between MRD kinetics and anti-leukemic specific T cells was observed. Cytokine Secretion Assays allowed to predominantly and respectively identify Effector Memory and Central Memory T cells among IFNγ–producing and IL2–producing T cells. Moreover, NPM1-mutated-specific CTLs against primary leukemic blasts or PHA-blasts pulsed with different peptide pools could be expanded ex vivo from NPM1-mutated AML patients or primed in healthy donors. We describe the spontaneous appearance and persistence of NPM1-mutated-specific T cells, which may contribute to the maintenance of long-lasting remissions. Future studies are warranted to investigate the potential role of both autologous and allogeneic adoptive immunotherapy in NPM1-mutated AML patients.

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“…Interestingly, it has been reported that the sequential induction of DNMT3A and nucleophosmin (NPM1) mutations in genetically engineered mice can generate an MPN-like disorder, following a condition of clonal hematopoiesis [23]. Nonetheless, NPM1 mutations are not found in MPNs in humans and are only exceptionally detected in non-acute myeloid neoplasms sharing dysplastic features (either purely myelodysplastic or myelodysplastic/myeloproliferative), multilineage involvement and excess of blasts, causing controversies about the pathological classification of these uncommon cases [24][25][26].…”

Section: Introductionmentioning

confidence: 99%

Inflammatory Microenvironment and Specific T Cells in Myeloproliferative Neoplasms: Immunopathogenesis and Novel Immunotherapies

Nasillo

Riva

Paolini

et al. 2021

IJMS

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The Philadelphia-negative myeloproliferative neoplasms (MPNs) are malignancies of the hematopoietic stem cell (HSC) arising as a consequence of clonal proliferation driven by somatically acquired driver mutations in discrete genes (JAK2, CALR, MPL). In recent years, along with the advances in molecular characterization, the role of immune dysregulation has been achieving increasing relevance in the pathogenesis and evolution of MPNs. In particular, a growing number of studies have shown that MPNs are often associated with detrimental cytokine milieu, expansion of the monocyte/macrophage compartment and myeloid-derived suppressor cells, as well as altered functions of T cells, dendritic cells and NK cells. Moreover, akin to solid tumors and other hematological malignancies, MPNs are able to evade T cell immune surveillance by engaging the PD-1/PD-L1 axis, whose pharmacological blockade with checkpoint inhibitors can successfully restore effective antitumor responses. A further interesting cue is provided by the recent discovery of the high immunogenic potential of JAK2V617F and CALR exon 9 mutations, that could be harnessed as intriguing targets for innovative adoptive immunotherapies. This review focuses on the recent insights in the immunological dysfunctions contributing to the pathogenesis of MPNs and outlines the potential impact of related immunotherapeutic approaches.

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NPM1 mutations may reveal acute myeloid leukemia in cases otherwise morphologically diagnosed as myelodysplastic syndromes or myelodysplastic/myeloproliferative neoplasms

Abstract: NPM1 mutations may reveal acute myeloid leukemia in cases otherwise morphologically diagnosed as myelodysplastic syndromes or myelodysplastic/myeloproliferative neoplasms

Cited by 25 publications

References 18 publications

Minimal/Measurable Residual Disease Monitoring in NPM1-Mutated Acute Myeloid Leukemia: A Clinical Viewpoint and Perspectives

Minimal/Measurable Residual Disease Monitoring in NPM1-Mutated Acute Myeloid Leukemia: A Clinical Viewpoint and Perspectives

Characterization and dynamics of specific T cells against nucleophosmin-1 (NPM1)-mutated peptides in patients with NPM1-mutated acute myeloid leukemia

Inflammatory Microenvironment and Specific T Cells in Myeloproliferative Neoplasms: Immunopathogenesis and Novel Immunotherapies

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