Acute Myeloid Leukemia (AML) with Mutated NPM1

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Primary Author(s)*

Xinjie Xu, PhD, FACMG

Cancer Category/Type

Acute Myeloid Leukemia (AML)

Cancer Sub-Classification / Subtype

Acute myeloid leukaemia (AML) with mutated NPM1

Definition / Description of Disease

NPM1 mutated AML is a distinct disease entity in the 2016 World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia.

Synonyms / Terminology

AML with cytoplasmic nucleophosmin

Epidemiology / Prevalence

Somatic mutations of NPM1 are observed in 22-18% of patients with de novo acute myeloid leukemia (AML), with a higher incidence (50-60%) in cytogenetically normal AML, making them one of the most frequent genetic alterations in AML[1][2][3].

The incidence of mutated NPM1 is much lower in other myeloid malignancies (5-6% of patients with chronic myelomonocytic leukemia and 2-5% of patients with myelodysplastic syndrome), however, it appears to increase after leukemic transformation (17% of CMML patients that progressed to AML and 9% of MDS-AML patients)[4][5][6][7][8].

More common in females

Clinical Features

Anemia, thrombocytopenia, high white blood cell and platelet counts

Sites of Involvement

Bone marrow, gingiva, lymph nodes and skin

Morphologic Features

Strong association with acute myelomonocytic and monocytic leukemia wich often have NPM1 nutations.

NPM1 mutations are also found in in AML with or without maturation and in pure erythroid leukemia.



IHC detection of cytoplasmic NPM1 expression is predictive on molecular mutation, because the morphological changes/staining are the result of the mutation effects in the cells.

Finding Marker
Positive (universal) EXAMPLE CD1
Positive (subset) EXAMPLE CD2
Negative (universal) EXAMPLE CD3
Negative (subset) EXAMPLE CD4

Chromosomal Rearrangements (Gene Fusions)

Rare gene fusions involving NPM1 genes (NPM1-MLF1 and NPM1–HAUS1) have been reported in patients with AML and are associated with cytoplasmic accumulation of NPM1[9][10][11].

Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence
EXAMPLE t(9;22)(q34;q11.2) EXAMPLE 3'ABL1 / 5'BCR EXAMPLE der(22) EXAMPLE 5%
EXAMPLE t(8;21)(q22;q22) EXAMPLE 5'RUNX1 / 3'RUNXT1 EXAMPLE der(8) EXAMPLE 5%

Characteristic Chromosomal Aberrations / Patterns

trisomy 8, deletion 9q

Genomic Gain/Loss/LOH

Gene Mutations (SNV/INDEL)

  • Studies investigating the methods by which NPM1 mutations lead to leukemogenesis show that NPM1 mutation alone is not sufficient to cause AML[12].
  • AML associated NPM1 mutations are generally frame-shift alterations at codons Trp288 and Trp290 with the most common alterations being 4-bp insertions that disrupt the NPM nucleolar-localization signal and generate a leucine-rich nuclear export signal, thus leading to abnormal cytoplasmic accumulation of NPM. In addition, a small subset of AML cases with NPM cytoplasmic localization by immunohistochemical staining did not harbor detectable NPM1 mutations[9], raising the possibility of alternative mechanisms for ectopic NPM expression.
  • 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[12][13]. Most mutations consist of a 4-base-pair insertion with >95% of mutations occurring between nucleotides 960 and 961 NM_002520[13]. The most common mutation (“type A”) involve duplication of TCTG (nucleotides 956-959 NM_002520), resulting in an insertion at position 960 NM_002520[13]. Type B and D mutations, which are also relatively common, both involve 4-base-pair insertions at position 960 NM_002520 [21]. NPM1 mutations cause increased nuclear exporting of NPM1 protein, compared to wild-type NPM1, hence increased cytoplasmic localization of the protein – ‘cytoplasmic NPM1’ (NPM1c)[12][14].
Gene Mutation Oncogene/Tumor Suppressor/Other Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) Prevalence (COSMIC/TCGA/Other)

Other Mutations

  • In NPM1 mutated AML, concurrent mutations have been found in DNMT3A (54%), NRAS (19%), TET2 (16%) and PTPN11 (15%)[3].
  • 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[12].
Type Gene/Region/Other
Concomitant Mutations DNMT3A, TET2, IDH1, IDH2, FLT3-ITD
Secondary Mutations Trisomy 8, del (9q)
Mutually Exclusive other AML with recurrent genetic abnormalities

Epigenomics (Methylation)

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Genes and Main Pathways Involved

  • The NPM1 gene encodes nucleophosmin (NPM), which is a multifunctional protein that shuttles between the nucleus and the cytoplasm, and binds many partners in distinct cellular compartments. It is involved in many cellular processes including ribosome biogenesis, maintenance of genomic stability and regulation of cellular proliferation.
  • Mutations in NPM1 represent a distinct entity in the World Health Organization (WHO) classification and commonly indicate a better risk prognosis[12]. Predominantly, observed NPM1 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)[12][14]. See Figure 3 in [12]. 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[15]. Without ARF, there is lack of MDM2 inhibition, leading to p53 inactivation by MDM2 and the loss of growth inhibition by p53[12]. In the context of NPM1 mutations, NPM1 haploinsufficiency results in uncontrolled centrosome duplication and consequently supernumerary centrosomes (a potential mechanism for tumor development)[16]. 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[12].

Diagnostic Testing Methods

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Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

  • Diagnosis based on identification of genetic lesion of NPM1 by immunohistochemical and /or molecular testing.
  • Mutated NPM1 is associated with a favorable prognosis in AML patients who do not have FLT3-internal tandem duplication (FLT3-ITD) mutations and with normal karyotype[2][3][17][18]. A more recent study found that NPM1-positive/FLT3-ITD-negative genotype predicts favorable outcomes in AML patients younger than 65 years, but not in those older than 65 years[19]. Besides FLT3-ITD, the prognostic impact of NPM1 mutations in AML can be modified by the presence of other concurrent mutations. In NPM1 mutated AML, concurrent mutations have been found in DNMT3A (54%), NRAS (19%), TET2 (16%) and PTPN11 (15%)[3]. DNMT3A missense mutations predicted shorter overall survival and higher cumulative incidence of relapse when stratified by NPM1 mutation status, whereas 'NRAS truncation mutations do not correlate with clinical outcome[20]. NRAS codon Gly12 and Gly13 mutations predict better overall survival in AML patients with concurrent NPM1 and DNMT3A mutations[3].
  • Minimal residual disease (MRD) monitoring of AML patients after chemotherapy provides important prognostic information[21][22]. Because NPM1 mutations are very stable over the course of disease, they are an excellent marker for monitoring minimal residual disease (MRD) for NPM1 mutated AML patients[11][23]. Indeed, several studies have suggested that MRD accessed by NPM1 mutation level using PCR-based methods is a strong independent predictor of higher relapse risk[18][24].

Familial Forms

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Other Information

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Edited by: Fabiola Quintero-Rivera 8/3/2018