Compendium of Cancer Genome Aberrations

Acute myeloid leukaemia with NPM1 mutation

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Haematolymphoid Tumours (WHO Classification, 5th ed.)

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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

WHO Classification of Disease

Structure Disease
Book Haematolymphoid Tumours (5th ed.)
Category Myeloid proliferations and neoplasms
Family Acute myeloid leukaemia
Type Acute myeloid leukaemia with defining genetic abnormalities
Subtype(s) Acute myeloid leukaemia with NPM1 mutation

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

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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[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%


editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).
Please incorporate this section into the relevant tables found in:
  • 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[2][3][12][13]. 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[14]. 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[15]. 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[16][17]. 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][18]. 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[13][19].

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).

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Characteristic Chromosomal Patterns

Put your text here (EXAMPLE PATTERNS: hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis. Do not delete table.)

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[20].
  • 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[20][21]. Most mutations consist of a 4-base-pair insertion with >95% of mutations occurring between nucleotides 960 and 961 NM_002520[21]. The most common mutation (“type A”) involve duplication of TCTG (nucleotides 956-959 NM_002520), resulting in an insertion at position 960 NM_002520[21]. 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)[20][22].
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%)[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[20].
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[20]. 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)[20][22]. See Figure 3 in [20]. 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[23]. Without ARF, there is lack of MDM2 inhibition, leading to p53 inactivation by MDM2 and the loss of growth inhibition by p53[20]. In the context of NPM1 mutations, NPM1 haploinsufficiency results in uncontrolled centrosome duplication and consequently supernumerary centrosomes (a potential mechanism for tumor development)[24]. 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[20].

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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  1. ↑ Courville, Elizabeth L.; et al. (2013). "Clinicopathologic analysis of acute myeloid leukemia arising from chronic myelomonocytic leukemia". Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc. 26 (6): 751–761. doi:10.1038/modpathol.2012.218. ISSN 1530-0285. PMID 23307061.
  2. ↑ 2.0 2.1 Falini, Brunangelo; et al. (2009). "Acute myeloid leukemia with mutated NPM1: diagnosis, prognosis and therapeutic perspectives". Current Opinion in Oncology. 21 (6): 573–581. doi:10.1097/CCO.0b013e3283313dfa. ISSN 1531-703X. PMID 19770764.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 Papaemmanuil, Elli; et al. (2016). "Genomic Classification and Prognosis in Acute Myeloid Leukemia". The New England Journal of Medicine. 374 (23): 2209–2221. doi:10.1056/NEJMoa1516192. ISSN 1533-4406. PMC 4979995. PMID 27276561.
  4. ↑ Bains, Ashish; et al. (2011). "FLT3 and NPM1 mutations in myelodysplastic syndromes: Frequency and potential value for predicting progression to acute myeloid leukemia". American Journal of Clinical Pathology. 135 (1): 62–69. doi:10.1309/AJCPEI9XU8PYBCIO. ISSN 1943-7722. PMID 21173125.
  5. ↑ Caudill, Jonathan S. C.; et al. (2006). "C-terminal nucleophosmin mutations are uncommon in chronic myeloid disorders". British Journal of Haematology. 133 (6): 638–641. doi:10.1111/j.1365-2141.2006.06081.x. ISSN 0007-1048. PMID 16704439.
  6. ↑ Dicker, F.; et al. (2010). "Mutation analysis for RUNX1, MLL-PTD, FLT3-ITD, NPM1 and NRAS in 269 patients with MDS or secondary AML". Leukemia. 24 (8): 1528–1532. doi:10.1038/leu.2010.124. ISSN 1476-5551. PMID 20520634.
  7. ↑ Ernst, Thomas; et al. (2010). "Transcription factor mutations in myelodysplastic/myeloproliferative neoplasms". Haematologica. 95 (9): 1473–1480. doi:10.3324/haematol.2010.021808. ISSN 1592-8721. PMC 2930947. PMID 20421268.
  8. ↑ Zhang, Yue; et al. (2007). "NPM1 mutations in myelodysplastic syndromes and acute myeloid leukemia with normal karyotype". Leukemia Research. 31 (1): 109–111. doi:10.1016/j.leukres.2006.03.013. ISSN 0145-2126. PMID 16678898.
  9. ↑ 9.0 9.1 Woolthuis, Carolien M.; et al. (2013). "A single center analysis of nucleophosmin in acute myeloid leukemia: value of combining immunohistochemistry with molecular mutation analysis". Haematologica. 98 (10): 1532–1538. doi:10.3324/haematol.2012.079806. ISSN 1592-8721. PMC 3789457. PMID 23716555.
  10. ↑ Campregher, Paulo Vidal; et al. (2016). "A novel mechanism of NPM1 cytoplasmic localization in acute myeloid leukemia: the recurrent gene fusion NPM1-HAUS1". Haematologica. 101 (7): e287–290. doi:10.3324/haematol.2015.137364. ISSN 1592-8721. PMC 5004474. PMID 27036161.
  11. ↑ 11.0 11.1 Falini, B.; et al. (2006). "Aberrant subcellular expression of nucleophosmin and NPM-MLF1 fusion protein in acute myeloid leukaemia carrying t(3;5): a comparison with NPMc+ AML". Leukemia. 20 (2): 368–371. doi:10.1038/sj.leu.2404068. ISSN 0887-6924. PMID 16341033.
  12. ↑ Schnittger, S.; et al. (2011). "Prognostic impact of FLT3-ITD load in NPM1 mutated acute myeloid leukemia". Leukemia. 25 (8): 1297–1304. doi:10.1038/leu.2011.97. ISSN 1476-5551. PMID 21537333.
  13. ↑ 13.0 13.1 Schnittger, Susanne; et al. (2009). "Minimal residual disease levels assessed by NPM1 mutation-specific RQ-PCR provide important prognostic information in AML". Blood. 114 (11): 2220–2231. doi:10.1182/blood-2009-03-213389. ISSN 1528-0020. PMID 19587375.
  14. ↑ Ostronoff, Fabiana; et al. (2015). "Prognostic significance of NPM1 mutations in the absence of FLT3-internal tandem duplication in older patients with acute myeloid leukemia: a SWOG and UK National Cancer Research Institute/Medical Research Council report". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 33 (10): 1157–1164. doi:10.1200/JCO.2014.58.0571. ISSN 1527-7755. PMC 4372852. PMID 25713434.
  15. ↑ Gale, Rosemary E.; et al. (2015). "Simpson's Paradox and the Impact of Different DNMT3A Mutations on Outcome in Younger Adults With Acute Myeloid Leukemia". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 33 (18): 2072–2083. doi:10.1200/JCO.2014.59.2022. ISSN 1527-7755. PMID 25964253.
  16. ↑ Grimwade, David; et al. (2014). "Defining minimal residual disease in acute myeloid leukemia: which platforms are ready for "prime time"?". Blood. 124 (23): 3345–3355. doi:10.1182/blood-2014-05-577593. ISSN 1528-0020. PMID 25049280.
  17. ↑ Hourigan, Christopher S.; et al. (2013). "Minimal residual disease in acute myeloid leukaemia". Nature Reviews. Clinical Oncology. 10 (8): 460–471. doi:10.1038/nrclinonc.2013.100. ISSN 1759-4782. PMC 4163748. PMID 23799371.
  18. ↑ Falini, B.; et al. (2009). "Altered nucleophosmin transport in acute myeloid leukaemia with mutated NPM1: molecular basis and clinical implications". Leukemia. 23 (10): 1731–1743. doi:10.1038/leu.2009.124. ISSN 1476-5551. PMID 19516275.
  19. ↑ Ivey, Adam; et al. (2016). "Assessment of Minimal Residual Disease in Standard-Risk AML". The New England Journal of Medicine. 374 (5): 422–433. doi:10.1056/NEJMoa1507471. ISSN 1533-4406. PMID 26789727.
  20. ↑ 20.0 20.1 20.2 20.3 20.4 20.5 20.6 20.7 20.8 Heath, E. M.; et al. (2017). "Biological and clinical consequences of NPM1 mutations in AML". Leukemia. 31 (4): 798–807. doi:10.1038/leu.2017.30. ISSN 1476-5551. PMID 28111462.
  21. ↑ 21.0 21.1 21.2 Falini, Brunangelo; et al. (2005). "Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype". The New England Journal of Medicine. 352 (3): 254–266. doi:10.1056/NEJMoa041974. ISSN 1533-4406. PMID 15659725.
  22. ↑ 22.0 22.1 Falini, Brunangelo; et al. (2006). "Immunohistochemistry predicts nucleophosmin (NPM) mutations in acute myeloid leukemia". Blood. 108 (6): 1999–2005. doi:10.1182/blood-2006-03-007013. ISSN 0006-4971. PMID 16720834.
  23. ↑ Colombo, Emanuela; et al. (2006). "Delocalization and destabilization of the Arf tumor suppressor by the leukemia-associated NPM mutant". Cancer Research. 66 (6): 3044–3050. doi:10.1158/0008-5472.CAN-05-2378. ISSN 0008-5472. PMID 16540653.
  24. ↑ Sportoletti, Paolo; et al. (2008). "Npm1 is a haploinsufficient suppressor of myeloid and lymphoid malignancies in the mouse". Blood. 111 (7): 3859–3862. doi:10.1182/blood-2007-06-098251. ISSN 0006-4971. PMC 2275037. PMID 18212245.

Notes

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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.

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