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A new type of NPM1 gene mutation in AML leading to a C-terminal truncated protein

Leukemia volume 21, pages 1564–1566 (2007)Cite this article

Identification and characterization of new somatic mutations in cancer-related genes during leukemogenesis are allowing to perform more accurate molecular classification of the diseases and subsequently, to select better risk-adapted therapies. Although the number and type of these gene alterations are continuously increasing, we still need a detailed picture of relevant changes that can give significant prognostic information. In acute myeloid leukaemia (AML), cytogenetically normal patients cluster a heterogeneous group with an intermediate-risk prognostic category. In recent years, several genetic alterations have been shown to affect clinical outcomes in this group of AML patients with normal karyotype (NK).1 Of relevant importance are FLT3 ITD and NPM1 mutations, which are present in around 30% and up to 60% respectively of AML-NK patients. Large leukaemia study groups have showed up association between NPM1 and FLT3 mutations regarding clinical outcome. Thus, most of the studies found that NPM1 mutations, in the absence of FLT3-ITD, are associated with a significantly improved outcome (most studies cited and reviewed by Mrózek et al.1 and Falini et al.2). The good prognostic mutations in NPM1 comprise changes in exon 12 of the gene, mainly consisting of a 4 bp duplication that causes a shift in the reading frame leading to a replacement of the last seven amino acids by 11 different ones in the C-terminal part of the protein. These alterations modify one or two critical Trp residues in the terminal part of the molecule and create a new nuclear export signal motif, causing delocalization of NPM1 protein from its normal nucleolar localization to the cytoplasm. This feature of the mutant proteins has also allowed detecting them by immunohistochemical methods, since ‘normal’ proteins are mainly located at the nucleolus while the ‘mutated’ are cytoplasmic. Since the first description of exon 12 mutations in NPM1 gene, more than 30 different 4 bp insertion or insertion/deletion have been described, leading all of them to a four-amino-acid longer protein with a new nuclear export signal motif.2

We report the detection of a new mutation caused by an eight nucleotide-insertion in NPM1 gene in a patient with AML-NK who suffered an early relapse of her disease. This alteration leads to a truncated protein lacking 20 amino acids at the C-terminal end. We discuss here the potential relevance of this alteration in the context of the still heterogeneous intermediate group of AML-NK.

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References

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Acknowledgements

We thank Drs C Suárez-Nieto, M Roza and A Román for support. This work was financed in part by a Grant from Fundación MMA-Investigación Médica. IS is a recipient of a research fellowship from Instituto Universitario de Oncologia. Instituto Universitario de Oncología is supported by Obra Social Cajastur-Asturias and Red de Centros de Cáncer-Instituto Carlos III-Spain

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Authors and Affiliations

  1. Laboratorio de Oncología Molecular, Hospital Universitario Central de Asturias & Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain

    A S Pitiot, I Santamaría, I Centeno & M Balbín

  2. Laboratorio de Apoyo a la Investigación del Banco de Tumores, Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain

    O García-Suárez & A Astudillo

  3. Servicio de Anatomía Patológica, Hospital Universitario Central de Asturias, Oviedo, Spain

    A Astudillo

  4. Servicio de Hematología, Hospital Universitario Central de Asturias, Oviedo, Spain

    C Rayón

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  1. A S Pitiot
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  2. I Santamaría
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Correspondence to M Balbín.

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Pitiot, A., Santamaría, I., García-Suárez, O. et al. A new type of NPM1 gene mutation in AML leading to a C-terminal truncated protein. Leukemia 21, 1564–1566 (2007). https://doi.org/10.1038/sj.leu.2404679

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