Nucleophosmin1 (NPM1) abnormality in hematologic malignancies, and therapeutic targeting of mutant NPM1 in acute myeloid leukemia

Chen, Yingyu; Hu, Jianda

doi:10.1177/2040620719899818

Cited by 36 publications

(22 citation statements)

References 132 publications

(195 reference statements)

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“…Finally, in AML with NPM1c+ expression, the capacity of NPM1c+ to delocalize in the cytosol crucial protein partners appears to be key to cellular transformation. In all cases, NPM1 is considered a promising therapeutic target [118,125] and many compounds, both natural and synthetic molecules, have been identified and are being developed as investigational drugs [118,125]. These molecules may target distinct structural domains of NPM1, thus affecting the ability of the protein to self-interact or interact with either protein or nucleic acid partners, with various consequences on its functional roles.…”

Section: Inhibitionmentioning

confidence: 99%

Nucleophosmin in Its Interaction with Ligands

Cela

Matteo

Federici

2020

IJMS

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Nucleophosmin (NPM1) is a mainly nucleolar protein that shuttles between nucleoli, nucleoplasm and cytoplasm to fulfill its many functions. It is a chaperone of both nucleic acids and proteins and plays a role in cell cycle control, centrosome duplication, ribosome maturation and export, as well as the cellular response to a variety of stress stimuli. NPM1 is a hub protein in nucleoli where it contributes to nucleolar organization through heterotypic and homotypic interactions. Furthermore, several alterations, including overexpression, chromosomal translocations and mutations are present in solid and hematological cancers. Recently, novel germline mutations that cause dyskeratosis congenita have also been described. This review focuses on NPM1 interactions and inhibition. Indeed, the list of NPM1 binding partners is ever-growing and, in recent years, many studies contributed to clarifying the structural basis for NPM1 recognition of both nucleic acids and several proteins. Intriguingly, a number of natural and synthetic ligands that interfere with NPM1 interactions have also been reported. The possible role of NPM1 inhibitors in the treatment of multiple cancers and other pathologies is emerging as a new therapeutic strategy.

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Section: Inhibitionmentioning

confidence: 99%

Nucleophosmin in Its Interaction with Ligands

Cela

Matteo

Federici

2020

IJMS

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“…Several newly reported genes regulated by SOX9 were identified, including NPM1, TXNRD1 and SDHD, which were upregulated, and NSD2, EIF4G1 and PYGL, which were downregulated by SOX9-knockdown. Mutations in NPM1 serve an important role in acute myeloid leukemia ( 24 , 25 ). NPM1 expression is upregulated in patients with TNBC, and NPM1-knockdown suppresses TNBC cell proliferation ( 26 ), suggesting that NPM1 acts as an oncogene in TNBC.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of SOX9 suppresses breast cancer cell proliferation and migration by regulating apoptosis and cell cycle arrest

Wang¹,

Dang²,

Luo³

et al. 2021

Oncol Lett

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SRY-related high-mobility group box 9 (SOX9) is an important transcriptional factor that regulates diverse genes involved in development and stemness. Dysregulation of SOX9 encourages carcinogenesis in various types of cancer, including breast cancer. The present study aimed to explore the role of SOX9 in triple-negative breast cancer (TNBC). SOX9 expression was significantly upregulated in the TNBC MDA-MB-231, MDA-MB-436 and MDA-MB-468 cell lines compared with that in BT-549 cells. Based on a lentivirus assay, SOX9 inhibition in MDA-MB-231 and MDA-MB-436 cells suppressed cell proliferation and colony formation. Apoptosis was increased and the cell cycle was arrested at the G 0 /G 1 phase in SOX9-knockdown cells. Transwell and wound-healing assays demonstrated that SOX9 inhibition decreased the migration and invasion of MDA-MB-231 and MDA-MB-436 cells. RNA sequencing identified that numerous genes were regulated by SOX9, including nucleophosmin, thioredoxin reductase 1, succinate dehydrogenase complex subunit D, nuclear receptor binding SET domain protein 2, eukaryotic translation initiation factor 4γ1 and glycogen phosphorylase L. Overall, the current study suggested that SOX9 acted as an oncogene in TNBC.

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“…This challenge is due to the fact that the difference between mutated NPM and wtNPM is restricted to a tetranucleotide insertion at the C‐terminus of mutated NPM , making the mutated part too small to be accurately reproduced for developing mutation‐specific antibody 25 . However, the mutant allele was found to procure wtNPM1 into the cytoplasm, for which several mechanisms were described, for example, dimerization between mutant and wtNPM1, or a nuclear export signal motif resulting from the mutation 3,26‐28 . So, if we adopt this concept, false‐positive results of the mutation are less likely to be caused by simple cross‐reaction with the wtNPM1 unless it was shuttled to the cytoplasm by undefined factors other than the mutated allele.…”

Section: Discussionmentioning

confidence: 99%

Flow cytometry in detection of Nucleophosmin 1 mutation in acute myeloid leukemia patients: A reproducible tertiary hospital experience

El-Gamal

Hashem

Habashy

et al. 2020

Int J Lab Hematology

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Introduction Nucleophosmin 1 (NPM1) mutation is one of the most frequent gene mutations in adult acute myeloid leukemia (AML), being detected in 35% of all cases and in up to 60% of patients with normal karyotype AML. AML with mutated NPM1 has distinct pathology, immunophenotyping, and confirmed favorable prognostic significance. Hence, AML with mutated NPM1 is a separate entity in the revised 2016 World Health Organization classification. This study aimed to evaluate the use of a reproducible flow cytometry approach in the assay of mutant NPM1 protein in AML patients and to correlate flow cytometric results with the NPM1 gene mutation. Methods Eighty‐nine newly diagnosed AML patients were evaluated for the expression of mutant NPM1 using flow cytometry and for the presence of NPM1 exon 12 mutations using high‐resolution melting polymerase chain reaction (HRM PCR). Results The NPM1 mutation was found in 35 (39.3%) patients by HRM PCR. These patients showed a significantly higher level of percentage of positive‐stained cells (% positive cells) and normalized median fluorescence intensity (MFI) for mutant NPM1 by flow cytometry than the negative mutation group. Conclusion Flow cytometric detection of mutant NPM1 offers a possible tool to indicate NPM1 mutational status.

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Nucleophosmin1 (NPM1) abnormality in hematologic malignancies, and therapeutic targeting of mutant NPM1 in acute myeloid leukemia

Cited by 36 publications

References 132 publications

Nucleophosmin in Its Interaction with Ligands

Nucleophosmin in Its Interaction with Ligands

Downregulation of SOX9 suppresses breast cancer cell proliferation and migration by regulating apoptosis and cell cycle arrest

Flow cytometry in detection of Nucleophosmin 1 mutation in acute myeloid leukemia patients: A reproducible tertiary hospital experience

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