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Review
. 2023 Feb 5;24(4):3161.
doi: 10.3390/ijms24043161.

Targeting and Monitoring Acute Myeloid Leukaemia with Nucleophosmin-1 (NPM1) Mutation

Lynn Chin  1 , Chantelle Ye Gwen Wong  1 , Harinder Gill  1
Affiliations
Review

Targeting and Monitoring Acute Myeloid Leukaemia with Nucleophosmin-1 (NPM1) Mutation

Lynn Chin et al. Int J Mol Sci. .

Abstract

Mutations in NPM1, also known as nucleophosmin-1, B23, NO38, or numatrin, are seen in approximately one-third of patients with acute myeloid leukaemia (AML). A plethora of treatment strategies have been studied to determine the best possible approach to curing NPM1-mutated AML. Here, we introduce the structure and function of NPM1 and describe the application of minimal residual disease (MRD) monitoring using molecular methods by means of quantitative polymerase chain reaction (qPCR), droplet digital PCR (ddPCR), next-generation sequencing (NGS), and cytometry by time of flight (CyTOF) to target NPM1-mutated AML. Current drugs, now regarded as the standard of care for AML, as well as potential drugs still under development, will also be explored. This review will focus on the role of targeting aberrant NPM1 pathways such as BCL-2 and SYK; as well as epigenetic regulators (RNA polymerase), DNA intercalators (topoisomerase II), menin inhibitors, and hypomethylating agents. Aside from medication, the effects of stress on AML presentation have been reported, and some possible mechanisms outlined. Moreover, targeted strategies will be briefly discussed, not only for the prevention of abnormal trafficking and localisation of cytoplasmic NPM1 but also for the elimination of mutant NPM1 proteins. Lastly, the advancement of immunotherapy such as targeting CD33, CD123, and PD-1 will be mentioned.

Keywords: acute myeloid leukaemia; nucleophosmin-1; targeted therapy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Genetic and functional characteristics of wild-type NPM1 protein. NES: Nuclear export signals, NLS: nuclear localisation signal, NoLS: Nucleolar localisation signal. Type A, B and D NPM1 mutations (denoted as NPM1-mut A, B, and D) with corresponding frequencies found in patients with NPM1-mutated AML: CDS mutation (the change that has occurred in the nucleotide sequence) leads to a frameshift, therefore, abolishing tryptophan (W) W288 and W298 at the c-terminal domain (usually present in wild-type NPM1 protein). AA mutation: amino acid mutation of W288Cfs*12 (tryptophan 288 to cysteine frameshift at exon 12).
Figure 2
Figure 2
NPM1 wild-type protein, and NPM1-mutant protein structural influences in nucleo-cytoplasmic relocation. Acidic regions influence binding to histone proteins, NLS: nuclear localisation signal binds to importin alpha and beta causing nuclear localisation, NoLS: Nucleolar localisation signals transport NPM1 to the nucleolus, W288, W298: Tryptophan stabilises NoLS and form a C-term helix structure, NES: Nuclear export signals interact with XPO1/CRM1 (chromosomal maintenance 1) protein resulting in an increase in cytoplasmic NPM1.
Figure 3
Figure 3
Targeted therapy for NPM1-mutated AML. (1) Anthracycline, (2) Cytarabine, (3) FLT3 inhibitors, (4) Gemtuzumab ozogamicin (GO), (5) Venetoclax, (6) Hypomethylating agents (Azacitidine), (7) Actinomycin D/Dactinomycin, (8) Arsenic trioxide and ATRA, (9) XPO1 inhibitors (Leptomycin) with cytoplasmic NPM1 (cNPM1), (10) Menin inhibitors disruption of Menin with histone methyltransferase MLL1 (KMT2A), Immunotherapy located on cell membrane: (11) HLA-dependent T cell immunotherapy, (12) CAR-T immunotherapy, (13) Anti-PD-1 immunotherapy, and (14) SYK inhibitor.
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Grants and funding

This research received no external funding.