• What is NPM1?
  • NPM1 in Acute Myeloid Leukemia
  • NPM1 Exon 12 Mutations
  • Clinical Trials


Nucleophosmin (NPM1, also known as nuclear phosphoprotein B23, numatrin) is a gene that encodes a phosphoprotein, which is involved in the regulation of the interactions of ARF and p53. Fusions, missense mutations, nonsense mutations, frameshift insertions and deletions, and in-frame deletions and insertions are observed in cancers such as acute myeloid leukemia and skin cancer.

Related Pathways

Last Updated: March 30, 2018

NPM1 in Acute Myeloid Leukemia

NPM1 mutations are observed in 25–41% of patients diagnosed with AML (Chou et al. 2006; Falini et al. 2005; Papaemmanuil et al. 2016; Suzuki et al. 2005; Thiede et al. 2006). "AML with mutated NPM1" is recognized as a separate entity under the 2016 World Health Organization (WHO) classification (Arber et al. 2016) and confers a favorable prognosis in the absence of FLT3-ITD mutations. However, these patients tend to be older in age and have a worse overall survival compared to other favorable-risk AML patients (Strickland et al. 2018). NPM1 mutations fall into class II of the "two-hit" theory of leukemogenesis.​

Last Updated: March 30, 2018

NPM1 Exon 12 Mutations in Acute Myeloid Leukemia

Location of mutation Chromosome 5, q35.1
Frequency of NPM1 mutations in AML 25–41% (Chou et al. 2006; Falini et al. 2005; Papaemmanuil et al. 2016; Suzuki et al. 2005; Thiede et al. 2006)
Frequency of NPM1 Exon 12 mutations in NPM1-mutated AML >99% (Falini et al. 2010)
Implications for Targeted Therapeutics
Response to FLT3 inhibitors Unknown at this time
Response to MEK inhibitors Unknown at this time
Response to JAK2 inhibitors Unknown at this time

Almost all NPM1 mutations in AML occur within exon 12 (Falini et al. 2010; Thiede et al. 2006; Verhaak et al. 2005) and mostly involve frameshift insertions. These mutations result in a sequence change and early truncation in the nuclear export signal (NES) motif of the protein NPM1, resulting in a stronger nuclear export signal leading to cytoplasmic localization of the protein. In comparison, the wild type protein localizes in the nucleolus. In the absence of FLT3-ITD, NPM1 mutations are associated with favorable prognosis in AML (Dohner et al. 2010; Dohner and Gaidzik 2011).

Preclinical studies have shown inhibitory activity of bortezomib and ixazomib in NPM1-mutated AML cell-lines (Garcia et al. 2016; Huang et al. 2012). Several clinical trials testing the efficacy of these drugs are currently in progress. ​

Last Updated: March 30, 2018

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