Frameshift mutations in exon 12 of the nucleophosmin gene (NPM1) result in aberrant cytoplasmic localization of the NPM protein (NPMc+) and occur in 25% to 35% of adult acute myeloid leukemia (AML). In adults with AML, NPMc+ has been associated with normal karyotype, FLT3/ITD mutations, high remission induction rates, and improved survival (particularly in patients lacking FLT3/ITD). NPMc+ has not been well characterized in childhood AML. This study examines the incidence and clinical significance of NPMc+ in 295 children with newly diagnosed AML treated on a large cooperative group clinical trial (POG-9421). We find that NPMc+ is relatively uncommon in childhood AML (23 of 295 patients, 8%); and is significantly associated with FLT3/ITD mutations (P = .046), female sex (P = .029), older age (P = .047), and normal cytogenetics (P < .001). There is a favorable impact of NPMc+ on survival in children lacking FLT3/ITD (5-year EFS, 69% vs 35%; hazard ratio, 0.39; P = .051), which is similar in magnitude to the favorable impact of t(8;21) and inv(16). We conclude that NPMc+ is relatively rare in childhood AML, particularly in younger children. NPMc+ does not abrogate the negative prognostic influence of FLT3/ITD mutations, but may contribute to risk stratification in children who lack FLT3/ITD mutations by identifying a group with superior prognosis.

Nucleophosmin (NPM) is a ubiquitously expressed chaperone protein that shuttles rapidly between the nucleus and cytoplasm, but predominantly resides in the nucleolus. It plays key roles in ribosome biogenesis, centrosome duplication, genomic stability, cell cycle progression and apoptosis. Somatic mutations in exon 12 of the NPM gene (NPM1) are the most frequent genetic abnormality in adult acute myeloid leukaemia (AML), found in approximately 35% of all cases and up to 60% of patients with normal karyotype (NK) AML. In children, NPM1 mutations are far less frequent, occurring in 8–10% of all AML cases, and in approximately 25% of those with a NK. NPM1 mutations lead to aberrant localization of the NPM protein into the cytoplasm, thus the designation, NPMc+ AML. NPMc+ AML is seen predominantly in patients with a NK and is essentially mutually exclusive of recurrent chromosomal translocations. Patients with NPM1 mutations are twice as likely as those who lack an NPM1 mutation to also have a FMS‐like tyrosine kinase (FLT3) internal tandem duplication (ITD) mutation. NPMc+ AML is also characterized by a unique gene expression signature and microRNA signature. NPMc+ AML has important prognostic significance, as NPMc+ AML, in the absence of a coexisting FLT3‐ITD mutation, is associated with a favourable outcome. NPM1 mutations have also shown great stability during disease evolution, and therefore represent a possible marker for minimal residual disease detection. Given its distinctive biologic and clinical features and its clear clinical relevance, NPMc+ AML is included as a provisional entity in the 2008 WHO classifications. There is still much to be learned about this genetic alteration, including its exact role in leukaemogenesis, how it interacts with other mutations and why it confers a more favourable prognosis. Further, it represents a potential therapeutic target warranting research aimed at identifying novel small molecules with activity in NPMc+ AML. Copyright © 2009 John Wiley & Sons, Ltd.

Key Points: Data from Dnmt3a−/− mice implicate Dot1l as a critical mediator of the malignant gene expression program of Dnmt3a-mediated leukemia. Pharmacologic inhibition of DOT1L exerts potent antileukemic activity in DNMT3A-mutant human acute myeloid leukemia in vitro and in vivo.

Pediatric Acute Lymphoblastic Leukemia (ALL) cure rates have improved exponentially over the past five decades with now over 90% of children achieving long-term survival. A direct contributor to this remarkable feat is the development and expanded understanding of combination chemotherapy. Asparaginase is the most recent addition to the ALL chemotherapy backbone and has now become a hallmark of therapy. It is generally accepted that the therapeutic effects of asparaginase is due to depletion of the essential amino acid asparagine, thus occupying a unique space within the therapeutic landscape of ALL. Pharmacokinetic and pharmacodynamic profiling have allowed a detailed and accessible insight into the biochemical effects of asparaginase resulting in regular clinical use of therapeutic drug monitoring (TDM). Asparaginase's derivation from bacteria, and in some cases conjugation with a polyethylene glycol (PEG) moiety, have contributed to a unique toxicity profile with hypersensitivity reactions being the most salient. Hypersensitivity, along with several other toxicities, has limited the use of asparaginase in some populations of ALL patients. Both TDM and toxicities have contributed to the variety of approaches to the incorporation of asparaginase into the treatment of ALL. Regardless of the approach to asparagine depletion, it has continually demonstrated to be among the most important components of ALL therapy. Despite regular use over the past 50 years, and its incorporation into the standard of care treatment for ALL, there remains much yet to be discovered and ample room for improvement within the utilization of asparaginase therapy.