title: The incidence and clinical significance of nucleophosmin mutations in childhood AML.
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.
authors: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA. pbrown2@jhmi.edu
authors: Patrick
authors: P
authors: Brown
authors: Emily
authors: E
authors: McIntyre
authors: Rachel
authors: R
authors: Rau
authors: Soheil
authors: S
authors: Meshinchi
authors: Norman
authors: N
authors: Lacayo
authors: Gary
authors: G
authors: Dahl
authors: Todd A
authors: TA
authors: Alonzo
authors: Myron
authors: M
authors: Chang
authors: Robert J
authors: RJ
authors: Arceci
authors: Donald
authors: D
authors: Small
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D002648:Child; D002675:Child, Preschool; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D018572:Disease-Free Survival; D005091:Exons / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D015994:Incidence; D007223:Infant; D007231:Infant, Newborn; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D000090243:Nucleophosmin; D012189:Retrospective Studies; D012307:Risk Factors; D012737:Sex Factors; D015996:Survival Rate; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics* / Q000378:metabolism
chemical_list: C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3