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Different types of NPM1 mutations in children and adults: evidence for an effect of patient age on the prevalence of the TCTG-tandem duplication in NPM1-exon 12

Leukemia volume 21, pages 366–367 (2007)Cite this article

Mutations of the nucleophosmin gene (NPM1) have been described as the single most frequent abnormality in adult patients with acute myeloid leukemia (reviewed in Falini et al.1). These mutations cluster in exon 12, coding for the COOH-terminal region of NPM1 and always induce a net insertion of four bases. The consecutive frameshift results in an elongated protein which contains an additional nuclear export signal and leads to an abnormal cytoplasmic localization of the protein.2 The most common type of mutation (type A), the duplication of the four bases TCTG, is found in approximatley 80% of all adult cases, but more than 40 additional mutations have been described.2, 3 In adult AML, NPM1 mutations were found to be associated with a distinct subgroup of patients with particular clinical (female sex, high WBC counts), morphological (cup-like morphology, lack of CD34 expression) and cytogenetic (normal karyotype) characteristics.1 In addition, several studies in adults have shown that NPM1-mutations represent an independent good prognostic marker, but only if not associated with FLT3-ITD mutations.1 Few data exist on the incidence and relevance of NPM1-mutations in children. The study by Cazzaniga et al.4 is the only report specifically investigating NPM1-mutations in pediatric AML. They found a low overall prevalence of 6.5% (7/107 patients), and showed that cases with NPM1 mutation were older and frequently had a normal karyotype. Only one additional study referred to NPM1-mutations in children, but did not further specify the pediatric patients.5

To gain further insight in the role of NPM1 in pediatric AML, we have investigated NPM1 mutations in a cohort of 75 children and young adults with AML (including one patient borderline to advanced MDS) treated in the AML98 and AML2004 protocols of the Berlin–Münster–Frankfurt (BFM) study group.6 DNA was extracted from cryopreserved cells and screened for NPM1 and FLT3 mutations using high resolution fragment analysis.7 Overall, 9/75 (12%) samples showed NPM1-mutations. As reported in adults,1 children with NPM1-mutations predominantly had a normal karyotype (NPM1-mut: 8/9; 89% compared to NPM1-wt: 30/56; 54%; P=0.069). Patients with NPM1 mutations were older (median age 13.2 vs 10.4 years) and – as shown in adults – predominantly had female sex (56 vs 33%). They frequently also showed an FLT3-ITD mutation (44 vs 23%), but due to the small number of cases, none of these associations was significant. Interestingly, all patients with NPM1 mutations are alive in remission (except one, who died before starting treatment from cerebral bleeding), irrespective of the FLT3-ITD status, but this has clearly to be interpreted with caution, due to the small number of patients.

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References

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  1. Medizinische Klinik und Poliklinik 1, Universitätsklinikum Carl Gustav Carus, Dresden, Germany

    C Thiede, E Creutzig & G Ehninger

  2. Department of Pediatric Hematology and Oncology, Medical High School Hannover, Hannover, Germany

    D Reinhardt

  3. Department of Pediatric Hematology and Oncology, University Children's Hospital, Muenster, Germany

    U Creutzig

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Thiede, C., Creutzig, E., Reinhardt, D. et al. Different types of NPM1 mutations in children and adults: evidence for an effect of patient age on the prevalence of the TCTG-tandem duplication in NPM1-exon 12. Leukemia 21, 366–367 (2007). https://doi.org/10.1038/sj.leu.2404519

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