Nucleophosmin 1 Mutations in Acute Myeloid Leukemia

Zarka, Jabra; Short, Nicholas J.; Kanagal‐Shamanna, Rashmi; Issa, Ghayas C.

doi:10.3390/genes11060649

Cited by 41 publications

(35 citation statements)

References 117 publications

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“…Studies have shown that the content of NPM1 in tumor cells and growing cells is significantly higher than that in quiescent cells (36,37). Overexpression of NPM1 can promote the growth and proliferation of various tumor cells (5)(6)(7)(8). These results suggest that NPM1 may be a potential target for tumor gene therapy.…”

Section: Discussionmentioning

confidence: 95%

“…Nucleophosmin 1 (NPM1) is a multifunctional protein that is mainly localized in nucleoli and shuttles between the nucleus and cytoplasm (3). In recent years, the focus of NPM1 research has gradually shifted from hematological diseases to solid tumors (4,5). Previous studies have demonstrated that NPM1 is overexpressed in several types of tumors and promotes the occurrence and progression of tumors (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

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NPM1 Is a Prognostic Biomarker Involved in Immune Infiltration of Lung Adenocarcinoma and Associated With m6A Modification and Glycolysis

et al. 2021

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BackgroundOverexpression of NPM1 can promote the growth and proliferation of various tumor cells. However, there are few studies on the comprehensive analysis of NPM1 in lung adenocarcinoma (LUAD).MethodsTCGA and GEO data sets were used to analyze the expression of NPM1 in LUAD and clinicopathological analysis. The GO/KEGG enrichment analysis of NPM1 co-expression and gene set enrichment analysis (GSEA) were performed using R software package. The relationship between NPM1 expression and LUAD immune infiltration was analyzed using TIMER, GEPIA database and TCGA data sets, and the relationship between NPM1 expression level and LUAD m6A modification and glycolysis was analyzed using TCGA and GEO data sets.ResultsNPM1 was overexpressed in a variety of tumors including LUAD, and the ROC curve showed that NPM1 had a certain accuracy in predicting the outcome of tumors and normal samples. The expression level of NPM1 in LUAD is significantly related to tumor stage and prognosis. The GO/KEGG enrichment analysis indicated that NPM1 was closely related to translational initiation, ribosome, structural constituent of ribosome, ribosome, Parkinson disease, and RNA transport. GSEA showed that the main enrichment pathway of NPM1-related differential genes was mainly related to mTORC1 mediated signaling, p53 hypoxia pathway, signaling by EGFR in cancer, antigen activates B cell receptor BCR leading to generation of second messengers, aerobic glycolysis and methylation pathways. The analysis of TIMER, GEPIA database and TCGA data sets showed that the expression level of NPM1 was negatively correlated with B cells and NK cells. The TCGA and GEO data sets analysis indicated that the NPM1 expression was significantly correlated with one m6A modifier related gene (YTHDF2) and five glycolysis related genes (ENO1, HK2, LDHA, LDHB and SLC2A1).ConclusionNPM1 is a prognostic biomarker involved in immune infiltration of LUAD and associated with m6A modification and glycolysis. NPM1 can be used as an effective target for diagnosis and treatment of LUAD.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

NPM1 Is a Prognostic Biomarker Involved in Immune Infiltration of Lung Adenocarcinoma and Associated With m6A Modification and Glycolysis

et al. 2021

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“…While in NK-AML patients, the mutation rate of it is higher, reaching 47% to 60%. [ 42 ] Schnittger et al [ 43 , 44 ] found that positive cases of NPM1 mutations are highly sensitive to chemotherapy-induced remission, complete remission (CR), LFS, and event-free survival. Therefore, the NPM1 gene mutation is considered to be an independent factor that predicts a good prognosis of AML.…”

Section: Discussionmentioning

confidence: 99%

The incidence and prognostic effect of Fms-like tyrosine kinase 3 gene internal tandem and nucleolar phosphoprotein 1 genes in acute myeloid leukaemia

Li¹,

Zhang²,

Li³

et al. 2020

Medicine

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Background: Molecular genotyping is an important prognostic role in acute myeloid leukemia (AML) patients. We aimed to design this meta-analysis to discuss the incidence and prognostic effect of nucleolar phosphoprotein 1 (NPM1) and Fms-like tyrosine kinase 3 gene internal tandem (FLT3-ITD) gene in AML patients. Methods: PubMed, Embase, Medline, and Cochrane library were systematically searched due to May 15, 2020. Four combinations of genotypes (FLT3-ITD neg /NPM1 mut , FLT3-ITD pos /NPM1 mut , FLT3-ITD neg /NPM1 wt , FLT3-ITD pos /NPM1 wt ) were compared in association with the overall survival (OS) and leukemia-free survival (LFS) outcome, which expressed as pooled hazard ratio (HR) and 95% confidence intervals (CIs). Results: Twenty-eight studies were included in our study. The incidence of FLT3-ITD neg /NPM1 mut , FLT3-ITD pos /NPM1 mut , FLT3-ITD neg /NPM1 wt , and FLT3-ITD pos /NPM1 wt was 16%, 13%, 50%, and 10%, respectively. The patients with FLT3-ITD neg /NPM1 mut gene may have the best OS and LFS when comparing with FLT3-ITD pos /NPM1 mut (HR = 1.94 and 1.70, P < .01), FLT3-ITD neg /NPM1 wt (HR = 1.57 and 2.09, P < .01), and FLT3-ITD pos /NPM1 wt (HR = 2.25 and 2.84, P < .001). Conclusion: AML patients with FLT3-ITD neg /NPM1 mut gene type have the best survival outcome than the other 3 gene types, which should be an independent genotyping in AML classification.

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“…This was paralleled by the cooperative impact of these two aberrations on gene expression profiles [23,25]. Interestingly, both FLT3-ITD and NPM1 were also previously shown to shape the epigenome in AML [22,26]. As the process of splicing occurs co-transcriptionally and its regulation was shown to be influenced by chromatin status (including modifications to both histones and DNA), by shaping the epigenome FLT3-ITD and NPM1 mutations have the potential to affect splicing [27][28][29].…”

Section: Introductionmentioning

confidence: 90%

“…FLT3-ITD rarely occurs alone and most frequently coincides with mutations in nucleophosmin (NPM1) with many FLT3-ITD+/NPM1+ AML patients eventually relapsing [1]. NPM1 is a multifunctional protein with diverse physiological roles that include regulation of the cell cycle, DNA damage repair, maintenance of genomic stability and stress response [22]. The molecular synergy between FLT3-ITD and NPM1 mutations was demonstrated to drive rapidly developing AML in mouse models [23,24].…”

Section: Introductionmentioning

confidence: 99%

Maturation State-Specific Alternative Splicing in FLT3-ITD and NPM1 Mutated AML

Wojtuszkiewicz

Werf

Hütter

et al. 2021

Cancers

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Despite substantial progress achieved in unraveling the genetics of AML in the past decade, its treatment outcome has not substantially improved. Therefore, it is important to better understand how genetic mutations translate to phenotypic features of AML cells to further improve response predictions and to find innovative therapeutic approaches. In this respect, aberrant splicing is a crucial contributor to the pathogenesis of hematological malignancies. Thus far, altered splicing is well characterized in relation to splicing factor mutations in AML. However, splicing profiles associated with mutations in other genes remain largely unexplored. In this study, we explored differential splicing profiles associated with two of the most common aberrations in AML: FLT3-ITD and NPM1 mutations. Using RNA-sequencing data of a total of 382 primary AML samples, we found that the co-occurrence of FLT3-ITD and mutated NPM1 is associated with differential splicing of FAB-type specific gene sets. Despite the FAB-type specificity of particular gene sets, the primary functions perturbed by differential splicing in all three FAB types include cell cycle control and DNA damage response. Interestingly, we observed functional divergence between alternatively spliced and differentially expressed genes in FLT3-ITD+/NPM1+ samples in all analyzed FAB types, with differential expression affecting genes involved in hematopoietic differentiation. Altogether, these observations indicate that concomitant FLT3-ITD and mutated NPM1 are associated with the maturation state-specific differential splicing of genes with potential oncogenic relevance.

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Nucleophosmin 1 Mutations in Acute Myeloid Leukemia

Cited by 41 publications

References 117 publications

NPM1 Is a Prognostic Biomarker Involved in Immune Infiltration of Lung Adenocarcinoma and Associated With m6A Modification and Glycolysis

NPM1 Is a Prognostic Biomarker Involved in Immune Infiltration of Lung Adenocarcinoma and Associated With m6A Modification and Glycolysis

The incidence and prognostic effect of Fms-like tyrosine kinase 3 gene internal tandem and nucleolar phosphoprotein 1 genes in acute myeloid leukaemia

Maturation State-Specific Alternative Splicing in FLT3-ITD and NPM1 Mutated AML

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