HAEM5:Acute myeloid leukaemia with NPM1 mutation

Haematolymphoid Tumours (WHO Classification, 5th ed.)

editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification

This page was converted to the new template on 2023-12-07. The original page can be found at HAEM4: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.

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).

More common in females

Clinical Features

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Signs and Symptoms	EXAMPLE: Asymptomatic (incidental finding on complete blood counts) EXAMPLE: B-symptoms (weight loss, fever, night sweats) EXAMPLE: Fatigue EXAMPLE: Lymphadenopathy (uncommon)
Laboratory Findings	EXAMPLE: Cytopenias EXAMPLE: Lymphocytosis (low level)

editv4:Clinical Features

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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.

Immunophenotype

POSITIVE:High CD33, low CD13, KIT,CD123,CD110 NEGATIVE: HLA-DR

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)

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Chromosomal Rearrangement	Genes in Fusion (5’ or 3’ Segments)	Pathogenic Derivative	Prevalence	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: t(9;22)(q34;q11.2)	EXAMPLE: 3'ABL1 / 5'BCR	EXAMPLE: der(22)	EXAMPLE: 20% (COSMIC) EXAMPLE: 30% (add reference)	Yes	No	Yes	EXAMPLE: The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).

editv4:Chromosomal Rearrangements (Gene Fusions)

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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.

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%

editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).

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• Chromosomal Rearrangements (Gene Fusions)
• Individual Region Genomic Gain/Loss/LOH
• Characteristic Chromosomal Patterns
• Gene Mutations (SNV/INDEL)

• 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. 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. 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%). 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. NRAS codon Gly12 and Gly13 mutations predict better overall survival in AML patients with concurrent NPM1 and DNMT3A mutations.

• Minimal residual disease (MRD) monitoring of AML patients after chemotherapy provides important prognostic information. 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. 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.

Individual Region Genomic Gain / Loss / LOH

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Chr #	Gain / Loss / Amp / LOH	Minimal Region Genomic Coordinates [Genome Build]	Minimal Region Cytoband	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: 7	EXAMPLE: Loss	EXAMPLE: chr7:1- 159,335,973 [hg38]	EXAMPLE: chr7	Yes	Yes	No	EXAMPLE: Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).
EXAMPLE: 8	EXAMPLE: Gain	EXAMPLE: chr8:1-145,138,636 [hg38]	EXAMPLE: chr8	No	No	No	EXAMPLE: Common recurrent secondary finding for t(8;21) (add reference).

editv4:Genomic Gain/Loss/LOH

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Characteristic Chromosomal Patterns

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Chromosomal Pattern	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: Co-deletion of 1p and 18q	Yes	No	No	EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).

editv4:Characteristic Chromosomal Aberrations / Patterns

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trisomy 8, deletion 9q

Gene Mutations (SNV / INDEL)

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Gene; Genetic Alteration	Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)	Prevalence (COSMIC / TCGA / Other)	Concomitant Mutations	Mutually Exclusive Mutations	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: TP53; Variable LOF mutations EXAMPLE: EGFR; Exon 20 mutations EXAMPLE: BRAF; Activating mutations	EXAMPLE: TSG	EXAMPLE: 20% (COSMIC) EXAMPLE: 30% (add Reference)	EXAMPLE: IDH1 R123H	EXAMPLE: EGFR amplification				EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).

Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

editv4:Gene Mutations (SNV/INDEL)

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• Studies investigating the methods by which NPM1 mutations lead to leukemogenesis show that NPM1 mutation alone is not sufficient to cause AML.

• 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, 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. Most mutations consist of a 4-base-pair insertion with >95% of mutations occurring between nucleotides 960 and 961 NM_002520. The most common mutation (“type A”) involve duplication of TCTG (nucleotides 956-959 NM_002520), resulting in an insertion at position 960 NM_002520. 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).

Gene	Mutation	Oncogene/Tumor Suppressor/Other	Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)	Prevalence (COSMIC/TCGA/Other)
EXAMPLE: TP53	EXAMPLE: R273H	EXAMPLE: Tumor Suppressor	EXAMPLE: LOF	EXAMPLE: 20%

Other Mutations

• In NPM1 mutated AML, concurrent mutations have been found in DNMT3A (54%), NRAS (19%), TET2 (16%) and PTPN11 (15%).

• 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.

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

Epigenomic Alterations

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Genes and Main Pathways Involved

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Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations	EXAMPLE: MAPK signaling	EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations	EXAMPLE: Cell cycle regulation	EXAMPLE: Unregulated cell division
EXAMPLE:  KMT2C and ARID1A; Inactivating mutations	EXAMPLE:  Histone modification, chromatin remodeling	EXAMPLE:  Abnormal gene expression program

editv4:Genes and Main Pathways Involved

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• 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. 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). See Figure 3 in . 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. Without ARF, there is lack of MDM2 inhibition, leading to p53 inactivation by MDM2 and the loss of growth inhibition by p53. In the context of NPM1 mutations, NPM1 haploinsufficiency results in uncontrolled centrosome duplication and consequently supernumerary centrosomes (a potential mechanism for tumor development). 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.

Genetic Diagnostic Testing Methods

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Familial Forms

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Additional Information

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Links

NPM1

References

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Notes

*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.

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

*Citation of this Page: “Acute myeloid leukaemia with NPM1 mutation”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 09/6/2024, https://ccga.io/index.php/HAEM5:Acute_myeloid_leukaemia_with_NPM1_mutation.