Blood Journal
Leading the way in experimental and clinical research in hematology

The incidence and clinical significance of nucleophosmin mutations in childhood AML

  1. Patrick Brown1,2,
  2. Emily McIntyre1,
  3. Rachel Rau1,
  4. Soheil Meshinchi3,4,
  5. Norman Lacayo5,
  6. Gary Dahl5,
  7. Todd A. Alonzo6,7,
  8. Myron Chang8,
  9. Robert J. Arceci1,2, and
  10. Donald Small1,2
  1. 1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD;
  2. 2Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD;
  3. 3Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA;
  4. 4Department of Pediatrics, University of Washington Medical Center, Seattle;
  5. 5Division of Pediatric Hematology/Oncology, Stanford University School of Medicine, Palo Alto, CA;
  6. 6University of Southern California Keck School of Medicine, Los Angeles;
  7. 7Children's Oncology Group, Arcadia, CA;
  8. 8Children's Oncology Group Statistical Office, Gainesville, FL


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.

  • Submitted February 26, 2007.
  • Accepted April 15, 2007.
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