Comment on Pasqualucci et al, page 4146
In this issue, Pasqualucci and colleagues show that the nucleophosmin (NPM1) mutation can be found in multiple myeloid lineages in AML, carrying implications for its cellular origins. They also suggest the recognition of this subset of AML in the World Health Organization (WHO) classification of myeloid neoplasms.
Our understanding of acute myeloid leukemia (AML) has improved dramatically in the past 2 years with the discovery by Falini et al1 that NPM1 is mutated in around half of cases with a normal karyotype, making it the most common molecular lesion identified in this disease to date. Although the functions of NPM1 are not completely understood, it is thought to play an important role in centrosome assembly, and has RNA binding and chaperone activity. The latter regulates the Arf-p53 pathway, suggesting that NPM1 has tumor-suppressor activity, a hypothesis supported by murine models of NPM1 loss of function.2 The various NPM1 mutations identified in AML are heterozygous and involve the C-terminal region encoded by exon 12. These not only disrupt key tryptophan residues that are required for localization to the nucleolus, but also generate a nuclear export signal leading to delocalization of mutant NPM1 to the cytoplasm where it sequesters residual wild-type protein from the nucleus.3 As an alternative to sequence analysis, the presence of an underlying NPM1 mutation can be inferred by immunohistochemistry, which shows an abnormal cytoplasmic localization of the protein in leukemic blasts.1,3
In this issue, Pasqualucci and colleagues have used antibodies that specifically detect wild-type or mutant forms of NPM1 in bone marrow trephine biopsy sections and have undertaken sequence analysis of DNA derived from laser-microdissected cells to investigate the cellular origins of the NPM1-mutated clone. Granulocytic, monocytic, erythroid, and megakaryocyte series were found to be involved, with at least 2 lineages harboring the mutation in more than 60% of the 161 NPM1-mutated cases analyzed. These findings are consistent with the NPM1 mutation arising in myeloid or multipotent progenitors and raise the distinct possibility that this may be a primary lesion in AML, present in the leukemic stem cell population. There is already some circumstantial evidence to support such a notion. Primary NPM1-mutation–positive leukemic cells can engraft in immunocompromised mice.4 Moreover, in cases where NPM1 and FLT3 are both mutated, multiple FLT3 internal tandem duplications (ITDs) can be detected within leukemic subpopulations on the background of a single NPM1 mutation, implying that the latter was the first lesion to arise.5 This is consistent with the observation that NPM1 mutation status tends to be more stable over the disease course than that of FLT3. NPM1 mutation is only rarely observed in AML with balanced translocations and is associated with distinct biologic features, gene expression profile, and a relatively favorable prognosis in the absence of FLT3-ITD.1,5,6 Together, these observations lend support to the recognition of a new category of AML.
The WHO classification has represented an important step forward, taking into account major advances in understanding of the etiology and molecular basis of AML, recognizing disease entities that demand differing management strategies.7 These include cases with chimeric oncoproteins generated as a result of recurrent cytogenetic abnormalities, which are currently restricted to t(8;21)/AML1-ETO, inv(16)/CBFB-MYH11, t(15;17) and variants, and t(11q23)/MLL rearrangements and which together account for approximately a third of cases arising in children and younger adults.7 It would seem to be in the spirit of the WHO classification to extend this category to include a wider range of molecular lesions that are fundamental to AML pathogenesis and relevant to its treatment. Hence, there appears to be a strong rationale for the development of a more inclusive category of “recurrent cytogenetic/molecular abnormalities.” Molecular screening for the NPM1 mutation is rapidly being introduced into the diagnostic workup of AML to enhance risk-stratified treatment approaches6; this will make this molecularly defined and cytogenetically cryptic entity, which is detected in approximately a third of AML cases, a prime candidate for recognition in future revisions to the WHO classification of myeloid neoplasms.
The author declares no competing financial interests. ▪
- Copyright © 2006 by The American Society of Hematology