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. 2007 Aug 1;110(3):979-85.
doi: 10.1182/blood-2007-02-076604. Epub 2007 Apr 17.

The incidence and clinical significance of nucleophosmin mutations in childhood AML

Patrick Brown  1 , Emily McIntyre, Rachel Rau, Soheil Meshinchi, Norman Lacayo, Gary Dahl, Todd A Alonzo, Myron Chang, Robert J Arceci, Donald Small
Affiliations

The incidence and clinical significance of nucleophosmin mutations in childhood AML

Patrick Brown et al. Blood. .

Abstract

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.

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Figures

Figure 1
Figure 1
SSCP gel demonstrating NPMc+ screening method. (Lane 12) NPM wild-type (NPMc−) control sample; (lane 13) NPMc+ control sample; (lanes 1-11) unknown samples. Lanes 4 and 11 contain samples confirmed to be NPMc+ by direct sequencing.
Figure 2
Figure 2
Incidence of NPMc+ according to age. NPMc+ is extremely rare in children younger than 3 years. In children 3 years or older, the incidence of NPMc+ is approximately 10% and does not vary significantly by age group.
Figure 3
Figure 3
Impact of NPMc+ and FLT3/ITD on survival. Kaplan-Meier estimates of event-free survival (EFS) and overall survival (OS) according to (A) NPMc+ and (B) FLT3/ITD. Log-rank P values are shown.
Figure 4
Figure 4
NPMc+ has prognostic value only in FLT3/ITD-negative subgroup. Kaplan-Meier estimates of event-free survival (EFS) and overall survival (OS) according to combination of NPMc+ and FLT3/ITD. Log-rank P values are shown.
Figure 5
Figure 5
NPMc+ is similar to t(8;21) and inv(16) in predicting favorable outcome in FLT3/ITD negative patients. Kaplan-Meier estimates of event-free survival (EFS) and overall survival (OS) in patients lacking FLT3/ITD mutations. Log-rank P values are shown.
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References

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