NPM1

Primary Author(s)*

Kay Weng Choy, MBBS, Monash Medical Centre

Synonyms

Nucleophosmin 1, Nucleolar Phosphoprotein B23, Nucleolar Protein NO38, Numatri

Genomic Location

Cytoband: 5q35.1

Genomic Coordinates:

chr5:170,814,120-170,838,141 (GRCh37/hg19)

chr5:171,387,116-171,411,137 (GRCh38/hg38)

Cancer Category/Type

HAEM4:Acute Myeloid Leukemia (AML) and Related Precursor Neoplasms

HAEM5:Acute myeloid leukaemia with NPM1 mutation

Gene Overview

• NPM1 encodes for nucleophosmin and belongs to the nucleophosmin/nucleoplasmin family of proteins [1]. The protein shuttles between the nucleolus, nucleus and cytoplasm, though it primarily stays in the nucleolus; in normal conditions, nuclear import of NPM1 predominates over export, and NPM1 is predominantly functionally active in the nucleolus. In the maintenance of genomic stability, NPM1 binds unduplicated centrosomes in the cytoplasm to prevent duplication, and dissociates to allow duplication; in this way, NPM1 acts as a licensing system for centrosome duplication by facilitating coordination with DNA replication and restricting centrosome duplication to once per cell cycle [2]. The N-terminal domain contains two nuclear export signal motifs. The central region contains two acidic regions spanning a bipartite nuclear localization signal. The C-terminal domain contains both the nuclear localization signal and the nucleolar localization signal [3,4]. See Figure 1 in [4].

• In ribosome biogenesis, NPM1 facilitates the export of pre-ribosomal proteins from the nucleus for incorporation into ribosomal subunits in the cytoplasms; as a chaperone, it coordinates the assembly of the large number of proteins required for ribosome biogenesis [3,4]. NPM1 also has histone chaperone function [4].

• NPM1 has a crucial role in modulating stress response and growth suppression by stabilizing p53 in the nucleus, as well as inhibiting MDM2 (mouse double minute 2 homolog) (a p53 E3-ubiquitin ligase that causes inactivation of p53), ultimately contributing to growth arrest [5,6]. NPM1 prevents degradation of Arf (Alternate reading frame protein). As a tumor suppressor, Arf suppresses cell growth by disrupting ribosomal RNA precursor processing and suppressing ribosome biogenesis [7]; Arf also localizes MDM2 to the nucleolus and therefore inhibits MDM2, consequently relieving p53 inhibition. [8]. NPM1 controls the transcriptional activity of Myc at target gene promoters and influences Myc suppression by facilitating degradation of Myc [9]; NPM1 is required to localize and stabilize Fbw7γ (an F-box protein component to the E3 ubiquitin ligase complex) which promotes Myc degradation. See Figure 2 in [4].

• In the cytoplasm, NPM1 inhibits the activated forms of caspase-6 and -8 and reduces caspase-induced apoptosis/cell death [10].

• Cytoplasmic NPM1 (NPM1c) in leukemogenesis
  • Mutations in NPM1 represent a distinct entity in the World Health Organization (WHO) classification and commonly indicate a better risk prognosis [4]. Predominantly, observed variants are sited in exon 12 and cause a frameshift in the C-terminal domain, affecting one or both of the key tryptophan residues in the domain. Such NPM1 mutations result in a ‘functionally stronger’ nuclear export than nuclear import signal (compared to wild-type NPM1) and thus there is cytoplasmic localization of the protein – ‘cytoplasmic NPM1’ (NPM1c) [4,11]. See Figure 3 in [4]. NPM1c sequesters ARF to the cytoplasm; however, unlike the ARF-NPM1 complex in the nucleolus, NPM1c is unable to stabilize ARF in the cytoplasm and consequently ARF becomes unstable and degrades [12]. Without ARF, there is lack of MDM2 inhibition, leading to p53 inactivation by MDM2 and the loss of growth inhibition by p53 [4]. In the context of NPM1 mutations, NPM1 haploinsufficiency results in uncontrolled centrosome duplication and consequently supernumerary centrosomes (a potential mechanism for tumor development) [13]. The loss of NPM1 function leads to activation of Myc oncogene (increased oncogene levels), promoting growth and cell proliferation. As expected, in the cytoplasm, NPM1c inhibits caspase-6/-8, promoting growth [4].
• NPM1 mutations and AML
  • NPM1 mutations are specific to AML. This was demonstrated in an immunohistochemical analysis of 980 non-AML hematopoietic or extrahematopoietic neoplasms in which NPM1 expression was restricted to the nucleus (in contrast, as discussed above, cytoplasmic restriction of NPM1 is unique to NPM1 mutations) [14].
  • Studies investigating the methods by which NPM1 mutations lead to leukemogenesis show that NPM1 mutation alone is not sufficient to cause AML [4]. The most prominent of the complex gene interactions is between NPM1, DNMT3A and FLT3-ITD (internal tandem duplication). The co-occurrence of these various mutations have differing prognostic implications [4].
  • In the setting of cytogenetically normal AML and in the absence of FLT3-ITD (internal tandem duplications), NPM1 mutations are associated with a “favorable” prognosis. There is evidence linking NPM1 mutations with positive response to induction therapy, high complete remission rates, event-free survival and/or overall survival [4,15].
  • NPM1 mutations are a stable marker of disease and therefore a potential molecular marker for monitoring minimal residual disease [4]. For example, one study found an association between persistence of NPM1-mutated transcripts in the peripheral blood following the second cycle of chemotherapy, and risk of relapse; patients in the NPM1-mutated subgroup were not only more likely to relapse than patients without NPM1-mutated transcripts, but also had lower survival rates [16].

Common Alteration Types

NPM1 is one of the most commonly mutated genes in AML, being present in 20-30% of AML cases [14]. In a study of 52 primary AML patients with cytoplasmic NPM1 (NPM1c), 98% of the subjects had exon 12 mutations; over 55 unique mutations have been identified in exon 12 [4,14]. Most mutations consist of a 4-base-pair insertion with >95% of mutations occurring between nucleotides 960 and 961 NM_002520 [14]. The most common mutation (“type A”) involve duplication of TCTG (nucleotides 956-959 NM_002520), resulting in an insertion at position 960 NM_002520 [14]. Type B and D mutations, which are also relatively common, both involve 4-base-pair insertions at position 960 NM_002520 [14]. NPM1 mutations cause increased nuclear exporting of NPM1 protein, compared to wild-type NPM1, hence increased cytoplasmic localization of the protein – ‘cytoplasmic NPM1’ (NPM1c) [4,11].

Internal Pages

HAEM5:Acute myeloid leukaemia with NPM1 mutation

External Links

NPM1 by Atlas of Genetics and Cytogenetics in Oncology and Haematology - detailed gene information

NPM1 by COSMIC - sequence information, expression, catalogue of mutations

NPM1 by CIViC - general knowledge and evidence-based variant specific information

NPM1 by Precision Medicine Knowledgebase (Weill Cornell) - manually vetted interpretations of variants and CNVs

NPM1 by Cancer Genetics Web - gene, pathway, publication information matched to cancer type

NPM1 by OncoKB - mutational landscape, mutation effect, variant classification

NPM1 by My Cancer Genome - brief gene overview

NPM1 by UniProt - protein and molecular structure and function

NPM1 by Pfam - gene and protein structure and function information

NPM1 by GeneCards - general gene information and summaries

References

1. Federici L, Falini B, (2013). Nucleophosmin mutations in acute myeloid leukemia: a tale of protein unfolding and mislocalization. Protein Sci 22(5):545-556. PMID 23436734.

2. Okuda M, et al., (2000). Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication. Cell 103(1):127-140. PMID11051553.

3. Yu Y, et al., (2006). Nucleophosmin is essential for ribosomal protein L5 nuclear export. Mol Cell Biol 26(10): 3798-3809. PMID 16648475.

4. Heath EM, et al., (2017). Biological and clinical consequences of NPM1 mutations in AML. Leukemia 31(4):798-807. PMID 28111462.

5. Colombo E, et al., (2002). Nucleophosmin regulates the stability and transcriptional activity of p53. Nat Cell Biol 4(7):529-533. PMID 12080348.

6. Kurki S, et al., (2004). Nucleolar protein NPM interacts with HDM2 and protects tumor suppressor protein p53 from HDM2-mediated degradation. Cancer Cell 5(5):465-475. PMID 15144954.

7. Bertwistle D, et al., (2004). Physical and functional interactions of the Arf tumor suppressor protein with nucleophosmin/B23. Mol Cell Biol 24(3):985-996. PMID 14729947.

8. Weber JD, et al., (1999). Nucleolar Arf sequesters Mdm2 and activates p53. Nat Cell Biol 1(1):20-26. PMID 10559859.

9. Li Z, et al., (2008). Nucleophosmin interacts directly with c-Myc and controls c-Myc-induced hyperproliferation and transformation. Proc Natl Acad Sci USA 105(48):18794-18799. PMID 19033198.

10. Leong SM, et al., (2010). Mutant nucleophosmin deregulates cell death and myeloid differentiation through excessive caspase-6 and -8 inhibition. Blood 116(17):3286-3296. PMID 20606168.

11. Falini B, et al., (2006). Immunohistochemistry predicts nucleophosmin (NPM) mutations in acute myeloid leukemia. Blood 108(6):1999-2005. PMID 16720834.

12. Colombo E, et al., (2006). Delocalization and destabilization of the Arf tumor suppressor by the leukemia associated NPM mutant. Cancer Res 66(6):3044-3050. PMID 16540653.

13. Sportoletti P, et al., (2008). Npm1 is a haploinsufficient suppressor of myeloid and lymphoid malignancies in the mouse. Blood 111(7):3859-3862. PMID 18212245.

14. Falini B, et al., (2005). Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med 352(3):254-266. PMID 15659725.

Notes

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