Changes

==Primary Author(s)*==

==Primary Author(s)*==

Kay Weng Choy MBBS

Kay Weng Choy, MBBS, Monash Medical Centre

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'''Genomic Coordinates:'''  

'''Genomic Coordinates:'''  

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

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

==Cancer Category/Type==

==Cancer Category/Type==

[[Acute Myeloid Leukemia (AML) and Related Precursor Neoplasms]]

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

[[Acute Myeloid Leukemia (AML) with Mutated NPM1]]

[[HAEM5:Acute myeloid leukaemia with NPM1 mutation]]

 

==Gene Overview==

==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].  

*''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].  

*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].

*''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].

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

* 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].

**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 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==

==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].

''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==

==Internal Pages==

[[Acute Myeloid Leukemia (AML) with Mutated NPM1]]

[[HAEM5:Acute myeloid leukaemia with NPM1 mutation]]

==External Links==

==External Links==

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.

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 ==

==Notes==

<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.

<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.

[[Category:Cancer Genes N]]

[[Category:Cancer Genes N]]