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ACUTE MYELOID LEUKEMIA

Molecular heterogeneity and measurable residual disease of rare NPM1 mutations in acute myeloid leukemia: a nationwide experience from the GBMHM study group

Leukemia volume 36, pages 1390–1400 (2022)Cite this article

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Nucleophosmin (NPM1)-mutated acute myeloid leukemia (AML) is a recognized entity related to distinctive biological, clinical, and prognostic features. Nearly all NPM1 variants are frame-shift mutations located in exon 11, inducing the insertion of a new nuclear export signal (NES) at the C-terminus end of the NPM1 protein, leading to its aberrant accumulation in the cytoplasm [1]. Although 90% of NPM1 mutations correspond to the three most frequent subtypes A, B, and D, more than 50 different mutations have already been described, but their impact on leukemia pathogenesis, patient prognosis, and therapeutic monitoring remains unclear.

The detection and quantification of NPM1-mutated (NPM1m) transcripts represents a specific marker for the molecular monitoring of measurable residual disease (MRD) in AML patients. An increase in NPM1m expression level between two time points is highly predictive of impending hematological relapse [2]. In addition, poor NPM1m-based MRD clearance after induction [3], consolidation [4], or hematopoietic stem cell transplantation [5] has been reported to be associated with a higher risk of relapse. Thus, NPM1m has become a decisive parameter for patient stratification and a guide for the development of new targeted therapies based on NPM1 status in AML [6]. However, in most laboratories MRD detection is restricted to the most frequent type A, B, and D mutations. Considering that approximately 10% of NPM1-mutated AML patients harbor a “rare” (non-A/B/D) variant [1], alternative approaches have been developed, mostly based on home-made allele-specific oligonucleotide (ASO)-real time quantitative-polymerase chain reaction (ASO-RT-qPCR) and droplet digital PCR (ddPCR) [2].

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Authors and Affiliations

  1. Université de Lille, CNRS, Inserm, CHU Lille, Laboratoire d’Hématologie, UMR9020-U1277 - Canther – Cancer Heterogeneity, Plasticity and Resistance to Therapies, F-59000, Lille, France

    Elise Fournier, Laurene Fenwarth, Alice Marceau-Renaut, Claude Preudhomme & Nicolas Duployez

  2. Hospices Civils de Lyon, Hopital Lyon Sud, Service clinique d’hématologie, Pierre-Bénite, France

    Maël Heiblig

  3. Hospices Civils de Lyon, Hôpital Lyon Sud, Service d’hématologie biologique, Pierre-Bénite, France

    Christine Lespinasse, Antoine Geay, Brigitte Soubeyrand, Adriana Plesa, Pierre Sujobert, Sandrine Hayette & Sarah Huet

  4. CHU Saint-Etienne, Hôpital Nord, Service d’hématologie biologique, Saint-Priest-en-Jarez, France

    Pascale Flandrin-Gresta

  5. CHU Strasbourg, Département de génétique moléculaire des cancers; Laboratoire d’hématologie, Hôpitaux universitaires de Strasbourg, INSERM, IRFAC, UMR-S1113, Strasbourg, France

    Laurent Miguet & Laurent Vallat

  6. Université Claude Bernard Lyon I, UR Lymphoma-Immuno-Biology, Faculté de médecine Lyon Sud, Oullins, France

    Pierre Sujobert, Sandrine Hayette & Sarah Huet

Authors
  1. Elise Fournier
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  2. Maël Heiblig
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  8. Laurent Vallat
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  9. Brigitte Soubeyrand
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  12. Claude Preudhomme
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  13. Pierre Sujobert
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  14. Sandrine Hayette
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  15. Nicolas Duployez
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  16. Sarah Huet
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Contributions

ND and SH (Huet) were responsible for designing the study. EF, AG, ND, and SH (Huet) conducted the literature search, extracted and analyzed the data, interpreted the results, wrote the manuscript and updated the reference lists. LF, CL, PFG, LM, LV, BS, and AMR contributed to the data extraction and analysis. MH, AP, CP, PS, SH, (Hayette) contributed to the data analysis and provided feedback on the manuscript.

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Correspondence to Sarah Huet.

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Fournier, E., Heiblig, M., Lespinasse, C. et al. Molecular heterogeneity and measurable residual disease of rare NPM1 mutations in acute myeloid leukemia: a nationwide experience from the GBMHM study group. Leukemia 36, 1390–1400 (2022). https://doi.org/10.1038/s41375-022-01534-z

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