NPM1 mutations in therapy-related acute myeloid leukemia with uncharacteristic features

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 ¼ 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 ¼ 0.0002 for both comparisons). Only 1 of 10 patients with NPM1 mutations presented chromosome aberrations characteristic of therapyrelated disease, and 7qÀ/À7, the most frequent abnormalities of t-MDS/t-AML, were not observed (P ¼ 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. Leukemia (2008) 22, 951-955;

Risk stratification using a new prognostic score for patients with secondary acute myeloid leukemia: results of the prospective AML96 trial

“…11,29 The incidence of mutated NPM1 in tAML in our series matches exactly the incidence in a previously published study. 30 Mutated NPM1 were found in mdsAML as well as in tAML that supposedly harbor more frequent cytogenetic abnormalities than de novo AML. 11,[30][31][32] As NPM1 mutations seem to occur mainly in de novo AML with normal karyotypes, some questions arise concerning their finding in other AML entities: there have been legitimate concerns whether this might indicate that NPM1-mutated tAML differs cytogenetically and molecularly from other tAML subtypes or whether those few reported cases of NPM1-mutated tAML represents in fact de novo NPM1-mutated AML incidentally arising in patients with a history of cytotoxic therapy.…”

“…30 Mutated NPM1 were found in mdsAML as well as in tAML that supposedly harbor more frequent cytogenetic abnormalities than de novo AML. 11,[30][31][32] As NPM1 mutations seem to occur mainly in de novo AML with normal karyotypes, some questions arise concerning their finding in other AML entities: there have been legitimate concerns whether this might indicate that NPM1-mutated tAML differs cytogenetically and molecularly from other tAML subtypes or whether those few reported cases of NPM1-mutated tAML represents in fact de novo NPM1-mutated AML incidentally arising in patients with a history of cytotoxic therapy. 33 Proposed data and models exist, favoring the hypothesis that NPM1 mutations are a 'primary event' in leukemogenesis 11 or are 'founder genetic alterations', defining a distinct AML entity.…”

Therapy-related acute myeloid leukaemia with mutated NPM1: treatment induced or de novo in origin?

“…The results from Andersen et al 7 also raise the intriguing question of whether their t-AML cases with mutated NPM1 are truly secondary leukaemias induced by previous treatment or whether they represent de novo NPM1-mutated AML arising in patients with a history of therapy. If NPM1-mutated t-AML is related to previous treatment, the close association with normal karyotype clearly indicates that the leukaemogenic mechanisms must differ from those that operate in t-AML carrying an abnormal karyotype.…”

“…Conversely, like t-AML carrying internal-tandem duplication of the MLL gene, 15 it is conceivable that a significant fraction of the t-AML reported by Andersen et al 7 are de novo leukaemias occurring incidentally in patients with a history of therapy. This is supported by the finding that these cases often received local radiotherapy or methotrexate plus prednisone, which are treatments whose leukaemogenic potential remains controversial.…”

“…1 De novo AML with mutated NPM1 shows a distinct immunophenotype 1 and gene expression profile, 9-11 which is characterized by CD34 downregulation (at RNA and protein levels) and upregulation of most HOX genes. Unfortunately, Andersen et al 7 were not able to provide any information on the HOX gene signature and CD34 protein expression in their cases. However, the few NPM1-mutated t-AML with normal karyotype so far investigated were usually negative for the CD34 molecule, 4 suggesting they may have the same immunophenotype (and possibly the same molecular signature) as NPM1-mutated AML arising de novo.…”