Gene Summary

Gene:NPM1; nucleophosmin 1
Aliases: B23, NPM
Summary:The protein encoded by this gene is involved in several cellular processes, including centrosome duplication, protein chaperoning, and cell proliferation. The encoded phosphoprotein shuttles between the nucleolus, nucleus, and cytoplasm, chaperoning ribosomal proteins and core histones from the nucleus to the cytoplasm. This protein is also known to sequester the tumor suppressor ARF in the nucleolus, protecting it from degradation until it is needed. Mutations in this gene are associated with acute myeloid leukemia. Dozens of pseudogenes of this gene have been identified. [provided by RefSeq, Aug 2017]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
Show (40)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Molecular Targeted Therapy
  • Acute Myeloid Leukaemia
  • Signal Transduction
  • Leukemic Gene Expression Regulation
  • RARA
  • Isocitrate Dehydrogenase
  • High-Throughput Nucleotide Sequencing
  • Apoptosis
  • Adolescents
  • NPM1
  • Peptides
  • Follow-Up Studies
  • Risk Assessment
  • Bone Marrow
  • Gene Expression
  • Non-Hodgkin Lymphoma
  • Cytogenetic Analysis
  • Nuclear Proteins
  • Cancer Gene Expression Regulation
  • Biomarkers, Tumor
  • Gene Expression Profiling
  • Remission Induction
  • Childhood Cancer
  • Proportional Hazards Models
  • Residual Disease
  • CCAAT-Enhancer-Binding Proteins
  • DNA (Cytosine-5-)-Methyltransferases
  • Referral and Consultation
  • Chromosome 5
  • Risk Factors
  • Genetic Predisposition
  • Antineoplastic Agents
  • Tissue Donors
  • Up-Regulation
  • Neoplasm Proteins
  • ALK
  • Disease-Free Survival
  • Recurrence
  • Myelodysplastic Syndromes
  • Karyotype
  • Cohort Studies
  • Leukaemia
  • DNA Mutational Analysis
  • Chromosome Aberrations
  • Mutation
  • Hematopoietic Stem Cell Transplantation
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: NPM1 (cancer-related)

Fuchs S, Naderi J, Meggetto F
Non-Coding RNA Networks in ALK-Positive Anaplastic-Large Cell Lymphoma.
Int J Mol Sci. 2019; 20(9) [PubMed] Free Access to Full Article Related Publications
Non-coding RNAs (ncRNAs) are essential regulators of gene expression. In recent years, it has become more and more evident that the different classes of ncRNAs, such as micro RNAs, long non-coding RNAs and circular RNAs are organized in tightly controlled networks. It has been suggested that deregulation of these networks can lead to disease. Several studies show a contribution of these so-called competing-endogenous RNA networks in various cancer entities. In this review, we highlight the involvement of ncRNA networks in anaplastic-large cell lymphoma (ALCL), a T-cell neoplasia. A majority of ALCL cases harbor the molecular hallmark of this disease, a fusion of the anaplastic lymphoma kinase (ALK) gene with the nucleophosmin (NPM, NPM1) gene leading to a permanently active kinase that promotes the malignant phenotype. We have focused especially on ncRNAs that are regulated by the

Cocciardi S, Dolnik A, Kapp-Schwoerer S, et al.
Clonal evolution patterns in acute myeloid leukemia with NPM1 mutation.
Nat Commun. 2019; 10(1):2031 [PubMed] Free Access to Full Article Related Publications
Mutations in the nucleophosmin 1 (NPM1) gene are considered founder mutations in the pathogenesis of acute myeloid leukemia (AML). To characterize the genetic composition of NPM1 mutated (NPM1

Li Y, Lv X, Ge X, et al.
Mutational spectrum and associations with clinical features in patients with acute myeloid leukaemia based on next‑generation sequencing.
Mol Med Rep. 2019; 19(5):4147-4158 [PubMed] Free Access to Full Article Related Publications
The aim of the present study was to examine the associations between 112 acute myeloid leukaemia (AML)‑associated genes and the prognosis and clinical features of AML using bioinformatics analysis in 62 patients with AML. A total of 61 gene mutations were identified, and ≥1 mutations were detected in 96.77% of the patients. A total of 11 frequent mutations were identified, including nucleophosmin 1 (NPM1), Fms related tyrosine kinase 3 (FLT3), DNA methyltransferase 3α (DNMT3A) and Notch 2 (NOTCH2), with a mutation rate of ≥10%. The FLT3 mutation was significantly associated with the white blood cell count at the time of diagnosis, and DNMT3A was significantly associated with the French‑American‑British subtype and cytogenetics of patients with AML. The FLT3, NPM1 and DNMT3A mutations were significantly associated with a poor overall survival (OS) in patients with AML. In addition, the co‑mutation of DNMT3A‑CCAAT enhancer binding protein α (CEBPA) was observed to be significantly associated with a poor OS in patients with AML. Furthermore, the functional enrichment analysis revealed that the co‑mutations of FLT3‑NOTCH2, SETBP1‑CREBBP and DNMT3A‑CEBPA were significantly enriched in processes of 'negative regulation of cell differentiation' and 'immune system development', indicating that these mutations may serve crucial roles in the diagnosis and treatment of AML.

Liao M, Liao W, Xu N, et al.
LncRNA EPB41L4A-AS1 regulates glycolysis and glutaminolysis by mediating nucleolar translocation of HDAC2.
EBioMedicine. 2019; 41:200-213 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: LncRNAs have been found to be involved in various aspects of biological processes. In this study, we aimed to uncover the molecular mechanisms of lncRNA EPB41L4A-AS1 in regulating glycolysis and glutaminolysis in cancer cells.
METHODS: The expression of EPB41L4A-AS1 in cancer patients was analyzed in TCGA and GEO datasets. The level of cellular metabolism was determined by extracellular flux analyzer. The relationship between p53 and EPB41L4A-AS1 was explored by qRT-PCR, luciferase assay and ChIP assay. The interactions between EPB41L4A-AS1 and HDAC2 or NPM1 were determined by RNA immunoprecipitation, RNA pull-down assay and RNA-FISH- immunofluorescence.
FINDINGS: EPB41L4A-AS1 was a p53-regulated gene. Low expression and deletion of lncRNA EPB41L4A-AS1 were found in a variety of human cancers and associated with poor prognosis of cancer patients. Knock down EPB41L4A-AS1 expression triggered Warburg effect, demonstrated as increased aerobic glycolysis and glutaminolysis. EPB41L4A-AS1 interacted and colocalized with HDAC2 and NPM1 in nucleolus. Silencing EPB41L4A-AS1 reduced the interaction between HDAC2 and NPM1, released HDAC2 from nucleolus and increased its distribution in nucleoplasm, enhanced HDAC2 occupation on VHL and VDAC1 promoter regions, and finally accelerated glycolysis and glutaminolysis. Depletion of EPB41L4A-AS1 increased the sensitivity of tumor to glutaminase inhibitor in tumor therapy.
INTERPRETATION: EPB41L4A-AS1 functions as a repressor of the Warburg effect and plays important roles in metabolic reprogramming of cancer.

Gambi G, Di Simone E, Basso V, et al.
The Transcriptional Regulator Sin3A Contributes to the Oncogenic Potential of STAT3.
Cancer Res. 2019; 79(12):3076-3087 [PubMed] Related Publications
Epigenetic silencing of promoter and enhancer regions is a common phenomenon in malignant cells. The transcription factor STAT3 is aberrantly activated in several tumors, where its constitutive acetylation accounts for the transcriptional repression of a number of tumor suppressor genes (TSG) via molecular mechanisms that remain to be understood. Using nucleophosmin-anaplastic lymphoma kinase-positive (NPM-ALK

Potter N, Miraki-Moud F, Ermini L, et al.
Single cell analysis of clonal architecture in acute myeloid leukaemia.
Leukemia. 2019; 33(5):1113-1123 [PubMed] Free Access to Full Article Related Publications
We used single cell Q-PCR on a micro-fluidic platform (Fluidigm) to analyse clonal, genetic architecture and phylogeny in acute myeloid leukaemia (AML) using selected mutations. Ten cases of NPM1c mutant AML were screened for 111 mutations that are recurrent in AML and cancer. Clonal architectures were relatively simple with one to six sub-clones and were branching in some, but not all, patients. NPM1 mutations were secondary or sub-clonal to other driver mutations (DNM3TA, TET2, WT1 and IDH2) in all cases. In three of the ten cases, single cell analysis of enriched CD34

Bejar R
What biologic factors predict for transformation to AML?
Best Pract Res Clin Haematol. 2018; 31(4):341-345 [PubMed] Related Publications
Transformation of myelodysplastic syndromes (MDS) into secondary acute myeloid leukemia (sAML) is defined by an arbitrary boundary of ≥20% bone marrow blasts but does not necessarily reflect a defined biological transition. The more obvious distinction lies between MDS patients that have an isolated bone marrow failure phenotype and those with excess blasts. Subtyping of MDS might be more accurately stratified into clonal cytopenias and oligoblastic leukemias, using the degree of dysplasia and blast percentage as risk features, respectively, rather than as diagnostic criteria. Transformation from MDS to sAML often involves clonal evolution or expansion of existing subclones that can be assessed by changes in variant allele frequencies of the somatic mutations that define them. There are a number of predictors for transformation that have been identified: these include mutations of genes in growth signaling pathways (NRAS, KRAS, PTPN11, FLT3), mutations in genes more commonly observed in AML (NPM1, WT1, IDH2), certain cytogenetic abnormalities (monosomy 7, complex karyotype, loss of 17p). Gene expression profiles that divide MDS into two major categories identify a progenitor gene signature subtype associated with a high risk of AML transformation. Assessing for these genetic abnormalities may better identify MDS patients at greatest risk of transformation.

Platzbecker U, Middeke JM, Sockel K, et al.
Measurable residual disease-guided treatment with azacitidine to prevent haematological relapse in patients with myelodysplastic syndrome and acute myeloid leukaemia (RELAZA2): an open-label, multicentre, phase 2 trial.
Lancet Oncol. 2018; 19(12):1668-1679 [PubMed] Related Publications
BACKGROUND: Monitoring of measurable residual disease (MRD) in patients with advanced myelodysplastic syndromes (MDS) or acute myeloid leukaemia (AML) who achieve a morphological complete remission can predict haematological relapse. In this prospective study, we aimed to determine whether MRD-guided pre-emptive treatment with azacitidine could prevent relapse in these patients.
METHODS: The relapse prevention with azacitidine (RELAZA2) study is an open-label, multicentre, phase 2 trial done at nine university health centres in Germany. Patients aged 18 years or older with advanced MDS or AML, who had achieved a complete remission after conventional chemotherapy or allogeneic haemopoietic stem-cell transplantation, were prospectively screened for MRD during 24 months from baseline by either quantitative PCR for mutant NPM1, leukaemia-specific fusion genes (DEK-NUP214, RUNX1-RUNX1T1, CBFb-MYH11), or analysis of donor-chimaerism in flow cytometry-sorted CD34-positive cells in patients who received allogeneic haemopoietic stem-cell transplantation. MRD-positive patients in confirmed complete remission received azacitidine 75 mg/m
FINDINGS: Between Oct 10, 2011, and Aug 20, 2015, we screened 198 patients with advanced MDS (n=26) or AML (n=172), of whom 60 (30%) developed MRD during the 24-month screening period and 53 (88%) were eligible to start study treatment. 6 months after initiation of azacitidine, 31 (58%, 95% CI 44-72) of 53 patients were relapse-free and alive (p<0·0001; one-sided binomial test for null hypothesis p
INTERPRETATION: Pre-emptive therapy with azacitidine can prevent or substantially delay haematological relapse in MRD-positive patients with MDS or AML who are at high risk of relapse. Our study also suggests that continuous MRD negativity during regular MRD monitoring might be prognostic for patient outcomes.
FUNDING: Celgene Pharma, José Carreras Leukaemia Foundation, National Center for Tumor Diseases (NCT), and German Cancer Consortium (DKTK) Foundation.

Assi SA, Imperato MR, Coleman DJL, et al.
Subtype-specific regulatory network rewiring in acute myeloid leukemia.
Nat Genet. 2019; 51(1):151-162 [PubMed] Free Access to Full Article Related Publications
Acute myeloid leukemia (AML) is a heterogeneous disease caused by a variety of alterations in transcription factors, epigenetic regulators and signaling molecules. To determine how different mutant regulators establish AML subtype-specific transcriptional networks, we performed a comprehensive global analysis of cis-regulatory element activity and interaction, transcription factor occupancy and gene expression patterns in purified leukemic blast cells. Here, we focused on specific subgroups of subjects carrying mutations in genes encoding transcription factors (RUNX1, CEBPα), signaling molecules (FTL3-ITD, RAS) and the nuclear protein NPM1). Integrated analysis of these data demonstrates that each mutant regulator establishes a specific transcriptional and signaling network unrelated to that seen in normal cells, sustaining the expression of unique sets of genes required for AML growth and maintenance.

Forghieri F, Comoli P, Marasca R, et al.
Minimal/Measurable Residual Disease Monitoring in
Int J Mol Sci. 2018; 19(11) [PubMed] Free Access to Full Article Related Publications
Acute myeloid leukemia (AML) with

Ibáñez M, Carbonell-Caballero J, Such E, et al.
The modular network structure of the mutational landscape of Acute Myeloid Leukemia.
PLoS One. 2018; 13(10):e0202926 [PubMed] Free Access to Full Article Related Publications
Acute myeloid leukemia (AML) is associated with the sequential accumulation of acquired genetic alterations. Although at diagnosis cytogenetic alterations are frequent in AML, roughly 50% of patients present an apparently normal karyotype (NK), leading to a highly heterogeneous prognosis. Due to this significant heterogeneity, it has been suggested that different molecular mechanisms may trigger the disease with diverse prognostic implications. We performed whole-exome sequencing (WES) of tumor-normal matched samples of de novo AML-NK patients lacking mutations in NPM1, CEBPA or FLT3-ITD to identify new gene mutations with potential prognostic and therapeutic relevance to patients with AML. Novel candidate-genes, together with others previously described, were targeted resequenced in an independent cohort of 100 de novo AML patients classified in the cytogenetic intermediate-risk (IR) category. A mean of 4.89 mutations per sample were detected in 73 genes, 35 of which were mutated in more than one patient. After a network enrichment analysis, we defined a single in silico model and established a set of seed-genes that may trigger leukemogenesis in patients with normal karyotype. The high heterogeneity of gene mutations observed in AML patients suggested that a specific alteration could not be as essential as the interaction of deregulated pathways.

Brunetti L, Gundry MC, Sorcini D, et al.
Mutant NPM1 Maintains the Leukemic State through HOX Expression.
Cancer Cell. 2018; 34(3):499-512.e9 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
NPM1 is the most frequently mutated gene in cytogenetically normal acute myeloid leukemia (AML). In AML cells, NPM1 mutations result in abnormal cytoplasmic localization of the mutant protein (NPM1c); however, it is unknown whether NPM1c is required to maintain the leukemic state. Here, we show that loss of NPM1c from the cytoplasm, either through nuclear relocalization or targeted degradation, results in immediate downregulation of homeobox (HOX) genes followed by differentiation. Finally, we show that XPO1 inhibition relocalizes NPM1c to the nucleus, promotes differentiation of AML cells, and prolongs survival of Npm1-mutated leukemic mice. We describe an exquisite dependency of NPM1-mutant AML cells on NPM1c, providing the rationale for the use of nuclear export inhibitors in AML with mutated NPM1.

Tien FM, Hou HA, Tsai CH, et al.
GATA2 zinc finger 1 mutations are associated with distinct clinico-biological features and outcomes different from GATA2 zinc finger 2 mutations in adult acute myeloid leukemia.
Blood Cancer J. 2018; 8(9):87 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
Mutations of the GATA binding protein 2 (GATA2) gene in myeloid malignancies usually cluster in the zinc finger 1 (ZF1) and the ZF2 domains. Mutations in different locations of GATA2 may have distinct impact on clinico-biological features and outcomes in AML patients, but little is known in this aspect. In this study, we explored GATA2 mutations in 693 de novo non-M3 AML patients and identified 44 GATA2 mutations in 43 (6.2%) patients, including 31 in ZF1, 10 in ZF2, and three outside the two domains. Different from GATA2 ZF2 mutations, ZF1 mutations were closely associated with French-American-British (FAB) M1 subtype, CEBPA double mutations (CEBPA

Thol F, Gabdoulline R, Liebich A, et al.
Measurable residual disease monitoring by NGS before allogeneic hematopoietic cell transplantation in AML.
Blood. 2018; 132(16):1703-1713 [PubMed] Related Publications
Molecular measurable residual disease (MRD) assessment is not established in approximately 60% of acute myeloid leukemia (AML) patients because of the lack of suitable markers for quantitative real-time polymerase chain reaction. To overcome this limitation, we established an error-corrected next-generation sequencing (NGS) MRD approach that can be applied to any somatic gene mutation. The clinical significance of this approach was evaluated in 116 AML patients undergoing allogeneic hematopoietic cell transplantation (alloHCT) in complete morphologic remission (CR). Targeted resequencing at the time of diagnosis identified a suitable mutation in 93% of the patients, covering 24 different genes. MRD was measured in CR samples from peripheral blood or bone marrow before alloHCT and identified 12 patients with persistence of an ancestral clone (variant allele frequency [VAF] >5%). The remaining 96 patients formed the final cohort of which 45% were MRD

Petrova L, Vrbacky F, Lanska M, et al.
IDH1 and IDH2 mutations in patients with acute myeloid leukemia: Suitable targets for minimal residual disease monitoring?
Clin Biochem. 2018; 61:34-39 [PubMed] Related Publications
OBJECTIVES: Molecular screening plays a major role in prognostic categorization and subsequent definition of treatment strategies for acute myeloid leukemia. The possibility of using IDH1/2 mutations as a marker for the monitoring of minimal residual disease (MRD) is still under investigation and remains unclear.
METHODS: In this retrospective study, we evaluated 90 patients with de novo AML using Sanger sequencing (exon 4, IDH1 and IDH2). For subsequent MRD monitoring were used both methods, massive parallel sequencing and droplet digital PCR (ddPCR).
RESULTS: We identified 22 patients (24%) who harboured mutations in IDH1 or IDH2 genes. Fourteen (64%) of them had other commonly used MRD markers (insertion in NPM1 and partial tandem duplication of MLL, MLL-PTD). Eight of the 22 patients had IDH1 mutations, 13 had IDH2 mutations and 1 had both IDH1 and IDH2 mutations. In our cohort, this IDH1/2 marker responded to the treatment in all of the patients and reflected the onset of the relapse very well. NPM1 mutation based MRD monitoring was more sensitive and predicted relapse earlier but IDH1/2 based monitoring was more sensitive than a method based on MLL-PTD. Both massive parallel sequencing and ddPCR were competent to monitor MRD using IDH1/2. Nevertheless, ddPCR was able to achieve a higher sensitivity in some cases and moreover this method can analyse a single sample without significant price increases.
CONCLUSION: Given these data, we conclude that IDH1/2 mutations can be used as a reliable and cost-effective marker for MRD monitoring.

Prutsch N, Gurnhofer E, Suske T, et al.
Dependency on the TYK2/STAT1/MCL1 axis in anaplastic large cell lymphoma.
Leukemia. 2019; 33(3):696-709 [PubMed] Related Publications
TYK2 is a member of the JAK family of tyrosine kinases that is involved in chromosomal translocation-induced fusion proteins found in anaplastic large cell lymphomas (ALCL) that lack rearrangements activating the anaplastic lymphoma kinase (ALK). Here we demonstrate that TYK2 is highly expressed in all cases of human ALCL, and that in a mouse model of NPM-ALK-induced lymphoma, genetic disruption of Tyk2 delays the onset of tumors and prolongs survival of the mice. Lymphomas in this model lacking Tyk2 have reduced STAT1 and STAT3 phosphorylation and reduced expression of Mcl1, a pro-survival member of the BCL2 family. These findings in mice are mirrored in human ALCL cell lines, in which TYK2 is activated by autocrine production of IL-10 and IL-22 and by interaction with specific receptors expressed by the cells. Activated TYK2 leads to STAT1 and STAT3 phosphorylation, activated expression of MCL1 and aberrant ALCL cell survival. Moreover, TYK2 inhibitors are able to induce apoptosis in ALCL cells, regardless of the presence or absence of an ALK-fusion. Thus, TYK2 is a dependency that is required for ALCL cell survival through activation of MCL1 expression. TYK2 represents an attractive drug target due to its essential enzymatic domain, and TYK2-specific inhibitors show promise as novel targeted inhibitors for ALCL.

Handschuh L, Wojciechowski P, Kazmierczak M, et al.
NPM1 alternative transcripts are upregulated in acute myeloid and lymphoblastic leukemia and their expression level affects patient outcome.
J Transl Med. 2018; 16(1):232 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
BACKGROUND: Expression of the NPM1 gene, encoding nucleophosmin, is upregulated in cancers. Although more than ten NPM1 transcripts are known, the reports were usually limited to one predominant transcript. In leukemia, the NPM1 expression has not been widely studied so far. In acute myeloid leukemia (AML), the mutational status of the gene seems to play a pivotal role in carcinogenesis. Therefore, the aim of the study was to quantify alternative NPM1 transcripts in two types of acute leukemia, AML and ALL (acute lymphoblastic leukemia).
METHODS: Using droplet digital PCR, we analyzed the levels of three protein-coding NPM1 transcripts in 66 samples collected from AML and ALL patients and 16 control samples. Using RNA-seq, we detected 8 additional NPM1 transcripts, including non-coding splice variants with retained introns. For data analysis, Welch two sample t-test, Pearson's correlation and Kaplan-Meier analysis were applied.
RESULTS: The levels of the particular NPM1 transcripts were significantly different but highly correlated with each other in both leukemia and control samples. Transcript NPM1.1, encoding the longest protein (294 aa), had the highest level of accumulation and was one of the most abundant transcripts in the cell. Comparing to NPM1.1, the levels of the NPM1.2 and NPM1.3 transcripts, encoding a 265-aa and 259-aa proteins, were 30 and 3 times lower, respectively. All three NPM1 transcripts were proportionally upregulated in both types of leukemia compared to control samples. In AML, the levels of NPM1 transcripts decreased in complete remission and increased again with relapse of the disease. Low levels of NPM1.1 and NPM1.3 were associated with better prognosis. The contribution of non-coding transcripts to the total level of NPM1 gene seemed to be marginal, except for one short 5-end transcript accumulated at high levels in AML and control cells. Aberrant proportions of particular NPM1 splice variants could be linked to abnormal expression of genes encoding alternative splicing factors.
CONCLUSIONS: The levels of the studied NPM1 transcripts were different but highly correlated with each other. Their upregulation in AML and ALL, decrease after therapy and association with patient outcome suggests the involvement of elevated NPM1 expression in the acute leukemia pathogenesis.

Chen S, He H, Wang Y, et al.
Poor prognosis of nucleophosmin overexpression in solid tumors: a meta-analysis.
BMC Cancer. 2018; 18(1):838 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
BACKGROUND: Nucleophosmin is a non-ribosomal nucleolar phosphoprotein that is found primarily in the nucleolus region of cell nucleus, plays multiple important roles in tumor processes. Accumulated previous studies have reported a potential value of NPM acted as a biomarker for prognosis in various solid tumors, but the results were more inconsistency. We performed this meta-analysis to precisely evaluate the prognostic significance of NPM in solid tumors.
METHODS: Clinical data were collected from a comprehensive literature search in PubMed, Web of Science, Embase, and China National Knowledge Infrastructure databases (up to October, 2017). A total of 11 studied with 997 patients were used to assess the association of NPM expression and patients' overall survival (OS). The hazard ratio (HR) or odds ratio (OR) with its 95% confidence intervals (CI) were calculated to estimate the effect.
RESULTS: The pooled results indicated that higher expression of NPM was observably correlated with poor OS in solid tumor (HR = 1.85, 95% CI: 1.44-2.38, P < 0.001). Furthermore, high expression of NPM was associated with some phenotypes of tumor aggressiveness, such as tumor stage (4 studies, III/IV vs. I/II, OR = 5.21, 95% CI: 2.72-9.56, P < 0.001), differentiation grade (poor vs. well/moderate, OR = 1.82, 95% CI: 1.01-3.27, P = 0.046).
CONCLUSION: This meta-analysis indicated that NPM may act as a valuable prognosis biomarker and a potential therapeutic target in human solid tumors.

Senapati P, Dey S, Sudarshan D, et al.
Oncogene c-fos and mutant R175H p53 regulate expression of Nucleophosmin implicating cancer manifestation.
FEBS J. 2018; 285(18):3503-3524 [PubMed] Related Publications
Nucleophosmin (NPM1) is a nucleolar protein that is frequently overexpressed in various types of solid tumors. NPM1 is involved in several cellular processes that might contribute significantly to the increased proliferation potential of cancers. Previous reports suggest that NPM1 expression is highly increased in response to mitogenic and oncogenic signals, the mechanisms of which have not been elucidated extensively. Using constructs incorporating different fragments of the NPM1 promoter upstream to a Luciferase reporter gene, we have identified the minimal promoter of NPM1 and candidate transcription factors regulating NPM1 promoter activity by luciferase reporter assays. We have validated the roles of a few candidate factors at the transcriptional and protein level by quantitative reverse transcriptase PCR, immunoblotting and immunohistochemistry, and explored the mechanism of regulation of NPM1 expression using immunoprecipitation and chromatin immunoprecipitation assays. We show here that the expression of NPM1 is regulated by transcription factor c-fos, a protein that is strongly activated by growth factor signals. In addition, mutant p53 (R175H) overexpression also enhances NPM1 expression possibly through c-myc and c-fos. Moreover, both c-fos and mutant p53 are overexpressed in oral tumor tissues that showed NPM1 overexpression. Collectively, our results suggest that c-fos and mutant p53 R175H positively regulate NPM1 expression, possibly in synergism, that might lead to oncogenic manifestation.

Martín I, Navarro B, Villamón E, et al.
Therapy-related acute myeloid leukemia developing 14 years after allogeneic hematopoietic stem cell transplantation, from a persistent R882H-DNMT3A mutated clone of patient origin.
Exp Mol Pathol. 2018; 105(1):139-143 [PubMed] Related Publications
BACKGROUND: Therapy-related acute myeloid leukemia (t-AML) develops in patients with prior exposure to cytotoxic therapies. Selection of a pre-existing TP53 mutated clone prone to acquire additional mutational events has been suggested as the main pathogenic mechanism of t-AML. Here, we report a unique case of t-AML which developed from a pre-existing DNMT3A mutated clone that persisted in the patient for more than 10 years despite treatment with intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (alloHSCT).
CASE PRESENTATION: A 42-year-old male was diagnosed with AML harboring a normal karyotype and mutations in the NPM1 (c.863_864ins, p.W288 fs*12), DNMT3A (c.2645G > A, p.R882H), and IDH1 (c.395G > A, p.R132H) genes. He achieved complete remission with intensive chemotherapy and was subsequently submitted to alloHSCT. Eleven years later, he was given chemotherapy and radiotherapy to treat a lung carcinoma. Three years later, t-AML was diagnosed; the disease had arisen from a pre-existing DNMT3A mutated patient-origin clone that had subsequently acquired a TP53 mutation and a complex karyotype. Although a second transplantation was intended, the disease was refractory to induction chemotherapy, and the patient eventually died from disease complications. We retrospectively demonstrated the persistence and post-transplantation latency of the R882H-DNMT3A mutation using a real-time PCR allele-specific analysis at different time-points during the observation period.
DISCUSSION AND CONCLUSION: The present case highlights the potential clinical implications of a R882H-DNMT3A mutated clone that persisted after conventional AML treatment, including alloHSCT. It also reinforces the notion of the importance of cell non-intrinsic factors, such as the hematopoietic-stress induced by chemotherapy and radiotherapy, as drivers of clonal expansion.

Akin DF, Oner DA, Kurekci E, Akar N
Determination of CEBPA mutations by next generation sequencing in pediatric acute leukemia.
Bratisl Lek Listy. 2018; 119(6):366-372 [PubMed] Related Publications
OBJECTIVES: The CCAAT/enhancer-binding protein-alpha (CEBPA) is lineage-specific transcription factor in the hematopoietic system. In this study, we aimed on the clinical features and the prognostic significance associated with CEBPA mutations in 30 pediatric patients with acute leukemia.
METHODS: In addition, the association between found variants and mutations of Ten-Eleven-Translocation 2 (TET2), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Casitas B-cell lymphoma (CBL), FLT3 (Fms-Related Tyrosine Kinase), JAK2 (Januse Kinase-2) and Nucleophosmin 1 (NPM1) were analyzed, which are important prognostic risk factors for pediatric acute leukemia patients. The entire CEBPA coding region was screened using the NGS method.
RESULTS: CEBPA mutations were detected in 16 (53.3 %) of 30 patients. In total, ten distinct of nucleotide changes were identified in 30 patients, including 6 novel and 4 known mutations by sequencing the entire CEBPA gene. We found 6 frame shift mutations, 1 missense mutation, 3 synonymous variants. The most common mutation was the c.487del G resulting p.Glu163Ser in 5 cases. Three patients carried CEBPA double mutations.
CONCLUSION: The detected variants in this article seemed to be the first screening results of genes studied by NGS in pediatric acute leukemia patients. Our results also showed some degree of association between FLT3-ITD, TET2, KRAS, CBL and CEBPA mutations (Tab. 4, Fig. 1, Ref. 24).

Parker BM, Parker JV, Lymperopoulos A, Konda V
A case report: Pharmacology and resistance patterns of three generations of ALK inhibitors in metastatic inflammatory myofibroblastic sarcoma.
J Oncol Pharm Pract. 2019; 25(5):1226-1230 [PubMed] Related Publications
BACKGROUND: Little exists currently in research about the mechanisms of resistance of ALK inhibitors in inflammatory myofibroblastic sarcoma. It is known, however, that ALK gene rearrangements are common in inflammatory myofibroblastic tumors, similar to non-small cell lung cancer. In roughly 50% of inflammatory myofibroblastic tumors, gene rearrangement has been found to occur on chromosome 2 at band 2p23. In non-small cell lung cancer, it has been shown that about a third of patients who progress on the first generation ALK inhibitor, crizotinib develops mutations in the ALK kinase domain. The remaining two-thirds of patients tend to develop amplification of ALK or activation of alternative signaling pathways. Chromoplexy has also been described as a mechanism of resistance, where multiple closed chain rearrangements cause loss-of-function of tumor suppressor genes and gain-in-function of oncogenic fusions. Partner genes that have been identified in IMTs are tropomyosin 3 (TPM3), tropomyosin 4 (TPM4), clathrin heavy chain (CLTC), Ran-binding protein 2 (RANBP2), cysteinyl-tRNA synthetase (CARS), 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC), and SEC31L1. All are active promoters for the fusion gene, in response to NPM binding. Several inflammatory myofibroblastic tumor case reports indicated that fusion of ALK and RANBP2 led to a more aggressive clinical course. Although the majority of inflammatory myofibroblastic tumor case reports have utilized first and second generation ALK inhibitors, all generations of ALK inhibitors have demonstrated some ability to impair disease progression and extend life expectancy. However, at some point in the course of therapy with each generation of ALK inhibitor, resistance ultimately developed. In order to better understand the pharmacology and resistance patterns behind three generations of ALK inhibitors, we sought to examine a patient with metastatic anaplastic lymphoma kinase-1-rearranged inflammatory myofibroblastic sarcoma to the brain. We also explored the similarities and differences of this clinical case to other inflammatory myofibroblastic sarcoma case reports involving the use of ALK inhibitors.
CASE REPORT: A rare case of pulmonary IMS with ALK-1 gene rearrangement and multiple brain metastases responded to three generations of ALK inhibitors. However, similar to other case reports, due to the development of resistance and recurrence, the patient eventually succumbed to the disease.
CONCLUSIONS: ALK inhibitors are beneficial in the temporary prevention of progression of disease in patients with inflammatory myofibroblastic tumors. In this case, due to the inability to reveal the fusion partner in this patient via DNA sequencing, it is unknown exactly if that partner was RANBP2 or another ALK partner gene. Brain biopsy tissue was also unobtainable during sequence of ALK due to risk versus benefit, which would have provided insight as which type of ALK resistance mutations the patient was developing. It is likely that this patient had some form of chromoplexy occurring.

Wu S, Dai Y, Zhang Y, et al.
Mutational spectrum and prognostic stratification of intermediate-risk acute myeloid leukemia.
Cancer Gene Ther. 2018; 25(7-8):207-213 [PubMed] Related Publications
The mutational spectrum and prognostic stratification of intermediate-risk acute myeloid leukemia (IR-AML), which accounts for a substantial number of AML, are unclear. In order to explore the prognostic significance of the mutational spectrum in IR-AML, 106 IR-AML patients were collected from The Cancer Genome Atlas database. Sixty-two patients underwent chemotherapy-only, forty-four proceeded to allogeneic hematopoietic stem cell transplantation (allo-HSCT). Fifty-five patients had more than five recurrent genetic mutations. NPM1 had the highest mutation frequency, followed by DNMT3A, FLT3, RUNX1, IDH2, IDH1, and TET2. In all patients, allo-HSCT was an independent favorable factor for EFS and OS (P = 0.036, P = 0.001, respectively); age ≥60 years, FLT3-ITD and mutations in DNMT3A and RUNX1 were independent risk factors for survival (all P < 0.05). In the chemotherapy-only group, multivariate analysis showed that age ≥60 years was an independent risk factor for EFS and OS (P = 0.008, P = 0.017, respectively). In the allo-HSCT group, multivariate analysis indicated that MLL-PTD was an independent risk fact for EFS (P = 0.037), FLT3-ITD and RUNX1 mutations independently contributed to poor OS (P = 0.035, P = 0.014, respectively). In conclusion, older age was an important risk factor for IR-AML patients undergoing chemotherapy-only; FLT3-ITD, MLL-PTD and RUNX1 mutations were significant risk factors for IR-AML patients who received allo-HSCT.

Zhang Y, Wang F, Chen X, et al.
Mutation profiling of 16 candidate genes in de novo acute myeloid leukemia patients.
Front Med. 2019; 13(2):229-237 [PubMed] Related Publications
This retrospective analysis aimed to investigate the mutation profile of 16 common mutated genes in de novo acute myeloid leukemia (AML) patients. A total of 259 patients who were diagnosed of de novo AML were enrolled in this study. Mutation profiling of 16 candidate genes were performed in bone marrow samples by using Sanger sequencing.We identified at least 1 mutation in 199 of the 259 samples (76.8%), and 2 or more mutations in 31.7% of samples. FLT3-ITD was the most common mutated gene (16.2%, 42/259), followed by CEBPA (15.1%, 39/259), NRAS (14.7%, 38/259), and NPM1 (13.5%, 35/259). Concurrence was observed in 97.1% of the NPM1 mutated cases and in 29.6% of the double mutated CEBPA cases. Distinct patterns of co-occurrence were observed for different hotspot mutations within the IDH2 gene: R140 mutations were associated with NPM1 and/or FLT3-ITD mutations, whereas R172 mutations co-occurred with DNMT3A mutations only. Concurrence was also observed in 86.6% of epigenetic regulation genes, most of which co-occurred with NPM1 mutations. The results showed certain rules in the mutation profiling and concurrence of AML patients, which was related to the function classification of genes. Defining the mutation spectrum and mutation pattern of AML will contribute to the comprehensive assessment of patients and identification of new therapeutic targets.

Ardestani MT, Kazemi A, Chahardouli B, et al.
FLT3-ITD Compared with DNMT3A R882 Mutation Is a More Powerful Independent Inferior Prognostic Factor in Adult Acute Myeloid Leukemia Patients After Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective Cohort Study
Turk J Haematol. 2018; 35(3):158-167 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
Objective: This study aimed to evaluate DNMT3A exon 23 mutations and their prognostic impacts in the presence of NPM1 and FLT3 mutations in acute myeloid leukemia (AML) patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT).
Materials and Methods: This study comprised 128 adult AML patients referred to the Hematology-Oncology and Stem Cell Research Center of Shariati Hospital. NPM1 and FLT3-ITD mutations were detected by fragment analysis. For DNMT3A exon 23 mutation analysis, we used Sanger sequencing. Overall survival (OS) and relapse-free survival (RFS) curves were estimated by the Kaplan-Meier method and the log-rank test was used to calculate differences between groups.
Results: The prevalence of DNMT3A exon 23 mutations was 15.6% and hotspot region R882 mutations were prominent. RFS and OS were compared in patients with and without DNMT3A exon 23 mutations using univariate analysis and there was no significant difference between these groups of patients. On the contrary, the FLT3-ITD mutation significantly reduced the OS (p=0.009) and RFS (p=0.006) in AML patients after allogeneic HSCT. In the next step, patients with AML were divided into four groups regarding FLT3-ITD and DNMT3A mutations. Patients with DNMT3A R882mut/FLT3-ITDpos had the worst OS and RFS. These results indicate that DNMT3A mutations alone do not affect the clinical outcomes of AML patients undergoing allogeneic HSCT, but when accompanied by FLT3-ITD mutations, the OS was significantly reduced (5-year OS 0% for DNMT3A R882mut/FLT3-ITDpos patients vs. 62% DNMT3A R882wt/FLT3-ITDneg, p=0.025) and the relapse rate increased.
Conclusion: It can be deduced that DNMT3A R882mut/FLT3-ITDpos is an unfavorable prognostic factor in AML patients even after allogeneic HSCT.

Suguna E, Farhana R, Kanimozhi E, et al.
Acute Myeloid Leukemia: Diagnosis and Management Based on Current Molecular Genetics Approach.
Cardiovasc Hematol Disord Drug Targets. 2018; 18(3):199-207 [PubMed] Related Publications
BACKGROUND & OBJECTIVE: Acute Myeloid Leukemia (AML) is characterized by the accumulation of ≥20% myeloid premature blast cells in the bone marrow and they are most often found in the peripheral blood. AML is generally classified based on either French-American-British (FAB) or World Health Organization (WHO) systems. For better clinical management, cytogenetic finding in AML is necessary and in patients with normal karyotypes - molecular, epigenetic and proteomic biomarkers are very important in choosing which drugs to prescribe. Mutations of certain genes like NPM1, FLT3, CEBPA, RUNX1 and MLL play a crucial role in the risk management and clinical stratification of AML patients. We reviewed the literature for the current trends of clinical practice based on laboratory based diagnostic tests in AML. Outcome and Result: We listed in AML chromosomal aberrations (translocations, fusions or RUNX1, CBFB, MYHI1, MLL, EVI1, PML-RARA), genes and mutations (NPM1, FLT3, CEPBA, MLL) epigenetic factors (DNMT34, TET2) and proteomic biomarkers (PTP, PTK, PIP) and analysed how on the basis of these factors medical risk was stratified and accordingly managed.
CONCLUSION: AML is genetically and functionally a heterogenous malignant disease. In the western world, leukemia is one of the most common among all cancers. India is ranked 3rd in cancer disease after United States of America and China. Cytogenetic analysis, molecular/proteomic biomarkers and epigenetic factors assist in determining the management strategies and prognosis of the disease. A number of targeted drugs in pre-clinical and clinical trials based on molecular factors and epigenetic mechanisms have been reported to have promising results in AML patients.

Min JW, Koh Y, Kim DY, et al.
Identification of Novel Functional Variants of SIN3A and SRSF1 among Somatic Variants in Acute Myeloid Leukemia Patients.
Mol Cells. 2018; 41(5):465-475 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
The advent of massively parallel sequencing, also called next-generation sequencing (NGS), has dramatically influenced cancer genomics by accelerating the identification of novel molecular alterations. Using a whole genome sequencing (WGS) approach, we identified somatic coding and noncoding variants that may contribute to leukemogenesis in 11 adult Korean acute myeloid leukemia (AML) patients, with serial tumor samples (primary and relapse) available for 5 of them; somatic variants were identified in 187 AML-related genes, including both novel (SIN3A, C10orf53, PTPRR, and RERGL) and well-known (NPM1, RUNX1, and CEPBA) AML-related genes. Notably, SIN3A expression shows prognostic value in AML. A newly designed method, referred to as "hot-zone" analysis, detected two putative functional noncoding variants that can alter transcription factor binding affinity near PPP1R10 and SRSF1. Moreover, the functional importance of the SRSF1 noncoding variant was further investigated by luciferase assays, which showed that the variant is critical for the regulation of gene expression leading to leukemogenesis. We expect that further functional investigation of these coding and noncoding variants will contribute to a more in-depth understanding of the underlying molecular mechanisms of AML and the development of targeted anti-cancer drugs.

Patel SS, Kuo FC, Gibson CJ, et al.
Blood. 2018; 131(25):2816-2825 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
Acute myeloid leukemia (AML) with mutated

Culen M, Kosarova Z, Jeziskova I, et al.
The influence of mutational status and biological characteristics of acute myeloid leukemia on xenotransplantation outcomes in NOD SCID gamma mice.
J Cancer Res Clin Oncol. 2018; 144(7):1239-1251 [PubMed] Related Publications
PURPOSE: This study aimed at analyzing the association of gene mutations and other acute myeloid leukemia (AML) characteristics with engraftment outcomes in immunodeficient mice and to select the engraftment outcomes that best reflect patient survival.
METHODS: Mutations in 19 genes as well as leukemia- and patient-related characteristics were analyzed for a group of 47 de novo AML samples with respect to three engraftment outcomes: engraftment ability, engraftment intensity (percentage of hCD45
RESULTS: For the 47 de novo samples, no single mutation influenced engraftment, whereas the NPM1
CONCLUSIONS: The engraftment of AML was influenced by mutation-interactions and other AML characteristics, rather than by single mutated genes, and engraftment intensity best reflected clinical penetrance of AML.

Suma S, Sakata-Yanagimoto M, Nguyen TB, et al.
Blastic plasmacytoid dendritic cell neoplasm arising from clonal hematopoiesis.
Int J Hematol. 2018; 108(4):447-451 [PubMed] Related Publications
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare subtype of myeloid neoplasm. Clonal evolution in the development of BPDCN remains to be elucidated. In the present study, we examined clonal evolution in a case of BPDCN by analyzing the distribution of gene mutations in tumor cells and non-tumor blood cells. The p.D1129fs and p.K1005fs TET2 mutations, p.P95H SRSF2 mutation, and p.L287fs NPM1 mutation were identified in a skin tumor at diagnosis and peripheral blood mononuclear cells at relapse. Notably, the p.D1129fs TET2 and p.L287fs NPM1 mutations were observed only in tumor cells, while the p.K1005fs TET2 and p.P95H SRSF2 mutations were found in both tumor cells and non-tumor blood cells. Recent genetic studies have suggested that some blood cancers may originate from clonal hematopoiesis, harboring somatic mutations. In the present case, the data suggest that BPDCN originated from clonal hematopoiesis with the p.K1005fs TET2 and p.P95H SRSF2 mutations via acquisition of the additional p.D1129fs TET2 and p.L287fs NPM1 mutations.

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