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

Abstract

Acute myeloid leukaemia (AML) carrying NPM1 mutations that cause aberrant cytoplasmic expression of nucleophosmin, 1,2 accounts for about one-third of de novo adult AML (50-60% of AML with normal karyotype), and shows distinctive biological and clinical features. 3 Until now, little information was available on the incidence of NPM1 mutations in therapyrelated AML (t-AML) or on the molecular and clinical characteristics of t-AML with mutated NPM1. 1,4-6 Thus, the first comprehensive study of t-MDS (t-myelodysplasia)/t-AML with mutated NPM1 reported by Andersen et al. 7 in this issue of the Journal is timely and remarkable.Andersen et al. 7 observed that NPM1 mutations occurred at lower frequency in t-AML than in de novo AML and were not related to any specific type of therapy. Notably, about 70% of the NPM1-positive t-MDS/t-AML had normal karyotype (an unusual finding in these cases, which generally show an abnormal karyotype) and none of them carried 7qÀ/À7, the most common abnormality in t-AML. 8 Finally, about half of t-MDS/t-AML with mutated NPM1 expressed the FLT3 internal tandem duplication.These findings are of great relevance since they indicate that t-AML with mutated NPM1 markedly differs cytogenetically and molecularly from other t-AML subtypes. Interestingly, normal karyotype and a high incidence of FLT3 internal tandem duplication are both distinctive features of NPM1-mutated AML with de novo origin. 1 The finding by Andersen et al. 7 that two t-AML with mutated NPM1 carried a ring chromosome 10 and a trisomy 8, respectively, is in keeping with the observation that about 14% of de novo AML with mutated NPM1 harbour chromosomal aberrations, which are thought to be secondary. 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. 1 Future efforts are warranted to clarify this issue.Thus, although some information is still missing, the evidence strongly suggests that de novo and therapy-related NPM1-mutated AML share common biological features. This finding is hardly surprising since t-AML with other recurrent genetic abnormalities, such as t(15;17) inv(16) or t(8;21), usually show the same biological and clinical findings as de novo AML with the corresponding karyotypes. 12 Rather, it further supports the view that NPM1 mutation is a founder genetic alteration, which defines a distinct leukaemia entity. 3 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 indu...

Prognostic significance of NPM1 mutations in acute myeloid leukemia: A meta-analysis

“…The reasons for excluding articles are shown in Fig. 1 (23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35).…”

Acute myeloid leukemia with mutated NPM1: diagnosis, prognosis and therapeutic perspectives

“…Therapy-related NPM1-mutated AML is quite rare and it presents features that differ from those of typical therapy-related AML [33 ]. Thus, it is not yet clear whether these cases represent true treatment-related AML or a de-novo NPM1-mutated AML occurring in patients with a history of treatment [34]. Simultaneous occurrence of AML with mutated NPM1 has been described in two members of the same family (father and daughter) but NPM1 mutations in these patients were somatic [35], unlike that observed in cases of familial AML with CEBPA mutations (germline in nature).…”

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

“…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. 34 Additionally, extensive studies were able to demonstrate that NPM1 mutations are most relevant in younger AML patients with normal karyotype and less frequent in patients with karyotype abnormalities.…”