¹Department of Clinical Genetics, Hematology/Oncology Section 4052, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

Correspondence: Dr MT Andersen, Department of Clinical Genetics, Hematology/Oncology Section 4052, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, Copenhagen DK-2100, Denmark. E-mail: morten.tolstrup.andersen@rh.regionh.dk

Received 17 October 2007; Revised 10 January 2008; Accepted 15 January 2008; Published online 14 February 2008.

Abstract

Frameshift mutations of the nucleophosmin gene (NPM1) were recently reported as a frequently occurring abnormality in patients with de novo acute myeloid leukemia (AML). To evaluate the frequency of NPM1 mutations in patients with therapy-related myelodysplasia (t-MDS) and therapy-related AML (t-AML), and their possible association to type of previous therapy and to other gene mutations, 140 patients with t-MDS or t-AML were analyzed for mutations of NPM1. NPM1 mutations were observed in 7 of 51 patients presenting as overt t-AML, as compared to only 3 of 89 patients presenting as t-MDS (P=0.037). The mutations were not related to any specific type of previous therapy, but they were significantly associated with a normal karyotype and mutations of FLT3 (P=0.0002 for both comparisons). Only 1 of 10 patients with NPM1 mutations presented chromosome aberrations characteristic of therapy-related disease, and 7q- /- 7, the most frequent abnormalities of t-MDS/t-AML, were not observed (P=0.002). This raises the question whether some of the cases presenting NPM1 mutations were in fact cases of de novo leukemia. The close association to class I mutations and the inverse association to class II mutations suggest mutations of NPM1 as representing a class II mutation-like abnormality in AML.