• Nucleophosmin (NPM1) is located on chromosome 5q35.1 and encodes a multifunctional protein predominantly located in the nucleolus but with shuttling capability to the nucleus and cytoplasm
• Mutations in NPM1 are associated with myeloid neoplasms, namely acute myeloid leukemia (AML)

• NPM1 mutations are frequently observed genetic abnormalities in AML, occurring in ~35% of all AML cases and in 50 - 60% of cases with normal karyotype (Blood 2020;136:1707, Leukemia 2022;36:2351, Blood Rev 2018;32:167)
• NPM1 mutated AML is strongly associated with myelomonocytic and monocytic morphology (Blood 2007;109:874)
• NPM1 mutations in AML are useful for measurable residual disease (MRD) monitoring due to frequency, stability at relapse and absence in subjects with clonal hematopoiesis (Int J Mol Sci 2018;19:3492, Blood 2021;138:2602)
• NPM1 mutations correlate with age, showing higher incidence as age increases (Hematol Oncol 2009;27:171)
• In pediatric AML cases, the frequency of NPM1 mutations (7.6%) is lower than observed in adult AML (25.4 - 41%)
  • In the pediatric group, NPM1 mutations independently predicted better outcomes, including cases with FLT3 / ITD mutations (Blood Cancer J 2020;10:1)

• Nuclear expression only: normal / wild type pattern
• Cytoplasmic expression is aberrant and supports underlying mutation (Appl Immunohistochem Mol Morphol 2013;21:205)
• Currently, there is no cut off for percentage or intensity of NPM1 cytoplasmic expression to predict mutation (Blood 2006;108:1999)

• In AML, mutated NPM1 in the context of normal karyotype and absence of FLT3 internal tandem duplication mutation has a more favorable prognosis (Dis Markers 2013;35:581)
• Multilineage dysplasia has no prognostic impact in NPM1 mutated AML (Blood 2010;115:3776)
• Prognostic biomarker in gastric cancer, in which NPM1 high expression groups are associated with a better overall survival rate (Neoplasma 2022;69:965)

Contributed by Leonie Frauenfeld, M.D.

Which of the following myeloid cell staining patterns strongly supports an underlying NPM1 mutation?

1. Golgi staining
2. Loss of expression
3. Membrane staining
4. Nuclear and cytoplasmic staining
5. Strictly nuclear staining

D. Nuclear and cytoplasmic staining. NPM1 is predominantly located in the nucleolus but has shuttling capability to the nucleus and cytoplasm. Nuclear and aberrant cytoplasmic NPM1 expression in neoplastic cells supports an underlying NPM1 mutation. Answers A and C are incorrect because NPM1 mutation leads to enhanced cytoplasmic staining, not Golgi or membrane staining. Answer B is incorrect because NPM1 is still detectable even if mutated. Answer E is incorrect because strictly nuclear staining is considered normal.

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Reference: NPM1

Which of the following morphologies is NPM1 mutated AML most frequently associated with?

1. Erythroblastic
2. Megakaryoblastic
3. Monocytic and myelomonocytic
4. Myeloid
5. Undifferentiated

C. Monocytic and myelomonocytic. NPM1 mutated AML is strongly associated with myelomonocytic and monocytic morphology (Blood 2007;109:874).

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Reference: NPM1