Changes

==Primary Author(s)*==

==Primary Author(s)*==

Dr Kay Weng Choy MBBS, BMedSci, FAACB, Monash Health

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==

Put your text here.

*''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].

 

 

Put your text here and/or fill in the table with an X where applicable

**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 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].

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==Common Alteration Types==

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''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].

! Copy Number Loss  !! Copy Number Gain  !!  LOH  !!  Loss-of-Function Mutation  !! Gain-of-Function Mutation  !!  Translocation/Fusion

==Internal Pages==

==Internal Pages==

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

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

==External Links==

==External Links==

==References==

==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.

#Arber DA, et al., (2008). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, Editors. IARC Press: Lyon, France, p117-118.

 

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.

#Li Y, et al., (2001). Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia. Nat Genet 28:220-221, PMID 11431691.

== 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.