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

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

==Gene Overview==

==Gene Overview==

* 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].

==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].

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].

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