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ACUTE MYELOID LEUKEMIA

The acidic stretch and the C-terminal nuclear export signal motif of NPM1 mutant: are they druggable in AML?

Leukemia volume 37, pages 2173–2175 (2023)Cite this article

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NPM1-mutated acute myeloid leukemia (AML) is the most common genetic type of adult AML (about 30%-35% of cases) [1] and, due to its distinctive molecular and clinico-pathological features [2, 3], is recognized as a new leukemia entity in the 2022 ICC [4] and WHO fifth edition [5] classifications of myeloid neoplasms. Two distinguishing biological characteristics of NPM1-mutated AML which are of potential relevance for its molecular targeted therapy are: (i) the high expression of HOX genes such as HOXA9 and MEIS1; [6] and (ii) the aberrant nuclear export of NPM1 in the cytoplasm of leukemic cells [1]. Upregulation of HOX genes and abnormal traffic of NPM1 can be targeted using menin inhibitors and XPO1 (CRM1) inhibitors, respectively [2, 3].

There is now evidence that a fraction of NPM1 mutant is localized to the nucleus of leukemia cells and is recruited to chromatin [7]. In particular, the high expression of HOX genes in NPM1-mutated AML is promoted by the interaction of the NPM1 mutant with chromatin-bound proteins, such as MLL1 and its co-factor menin [8]. Menin inhibitors disrupt the menin-MLL1 network leading to a loss of NPM1 mutant from chromatin, demonstrating that this inhibitor has a direct effect on the oncogene’s function [7]. Menin inhibitors have shown strong anti-leukemic activity in KMT2A-rearranged and NPM1-mutated AML, both in vitro and in vivo [8, 9]. In patients, the menin inhibitor revumenib has resulted into 21% of complete remissions in NPM1-mutated AML, frequently associated with minimal measurable disease (MRD) negativity, down-regulation of MEIS and HOXA9 genes and increased expression of CD14 [10]. Ziftomenib, another menin inhibitor, has resulted in 35% CR (75% MRD-negative) in NPM1-mutated AML [11]. Unlike revumenib, ziftomenib was associated with higher frequency of differentiation syndrome [11].

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Fig. 1: Application of the Abd technology to the NPM1 mutant.

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Acknowledgements

This work was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC IG 2019 number 23604) and the European Research Council (Advanced Grant 2016 number 740230).

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Authors and Affiliations

  1. Institute of Hematology and Center for Hemato-Oncological research (CREO), University of Perugia and Santa Maria della Misericordia Hospital, Perugia, Italy

    Brunangelo Falini

  2. Centre for Cancer Biomarkers (CCBIO), Department of Clinical Science, University of Bergen, Bergen, Norway

    Bjorn T. Gjertsen & Vibeke Andresen

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BF coordinated the study and all authors contributed to wrote the manuscript.

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Correspondence to Brunangelo Falini.

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Conflict-of-interest disclosure: BF holds a patent on NPM1 mutants (number 102004901256449). The remaining authors declare no competing financial interests.

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Falini, B., Gjertsen, B.T. & Andresen, V. The acidic stretch and the C-terminal nuclear export signal motif of NPM1 mutant: are they druggable in AML?. Leukemia 37, 2173–2175 (2023). https://doi.org/10.1038/s41375-023-02037-1

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