Chou WC, Tang JL, Lin LI, et al. Nucleophosmin mutations in de novo acute myeloid leukemia: the age-dependent incidences and the stability during disease evolution. Cancer Res 2006;66:3310-6. Gorello P, Cazzaniga G, Alberti F, et al. Quantitative assessment of minimal residual disease in acute myeloid leukemia carrying nucleophosmin (NPM1) gene mutations. Leukemia 2006; [Epub ahead of print].

Acute myeloid leukemia (AML) is a highly heterogeneous disease both from a clinical and genetic point of view. Mutations in the nucleophosmin gene (NPM1) in AML were discovered in These mutations are seen in as many as one-third of cases, representing the most prevalent gene mutations in AML today. NPM1 mutations are reported to occur in 45 percent of cases of AML with normal karyotypes. NPM1 mutations are highly prevalent (60 percent) in association with the second-most-frequent category of FLT3 mutations in AML, the mutations of the so-called fms-like receptor tyrosine. FLT3 mutations express negative prognostic value (relapse, survival), but, in contrast, NPM1 mutations express favorable prognostic impact. NPM1 is a phosphoprotein that shuttles between nucleus and cytoplasm with physiologic functions that are thought to be multifold. Recent studies in NPM1 genetic mouse models show that its loss of function leads to loss of tumor suppression because NPM1 is involved in the p53 and p19ARF pathway and maintenance of genomic integrity. The mutations affect exon 12 and usually lead to frame shifts that dislocate NPM from the nucleus, which determines the abnormal cytoplasmic retention of mutated NPM1.

The fact that NPM1 mutations are so frequently seen in AML has raised the question of the potential usefulness of NPM1 mutations as a marker for disease activity. Before the publication of these papers, a few recent studies had already shown stable mutations in direct comparisons of AML specimens at diagnosis and relapse, but those studies had not provided serial follow-up measurements.

Two recent papers by Chou et al. and Gorello et al. offer longitudinal monitoring with NPM1 quantitative polymerase chain reactions (PCR). The results of both studies suggest that NPM1 may furnish a convenient and stable marker for quantitative disease measurements during follow-up. In the first, Chou and colleagues found that none of 28 patients without NPM1 mutations acquired new mutations during a median follow-up interval of 16 months, while among 13 patients with AML and mutant NPM1, the mutations disappeared in all cases during complete remission. In all five NPM1-positive patients who relapsed, the same NPM1 mutations reappeared. Thus, NPM1 disappears during complete remission and comes back as the same abnormality at the time of relapse. The authors also found that in one patient with AML and NPM1 mutation, the mutation was no longer detected at second relapse. In the second paper, Goello et al. found that of 10 patients attaining complete remission, real-time quantitative PCR of NPM1 cDNA revealed a sharp decline of NPM1 mutated copies. Furthermore, in four of these, a subsequent increase in NPM1 copies closely correlated with relapse. The conclusions from the two studies are still preliminary, as the numbers of patients with adequate longitudinal follow up are small. The monitoring of minimal residual leukemia throughout treatment during morphological complete remission might provide an important strategy in clinical practice for decisions regarding treatment discontinuation and a timely treatment switch. Clearly, these early observations in two small series of patients need confirmation and extension.

Competing Interests

Dr. Löwenberg indicated no relevant conflicts of interest.