TY - JOUR
T1 - Influence of Nucleophosmin (
NPM1) Genotypes on Outcome of Patients With AML
T2 - An AIEOP-BFM and COG-SWOG Intergroup Collaboration.
AU - Tregnago, Claudia
AU - Benetton, Maddalena
AU - Ries, Rhonda E
AU - Peplinski, Jack H
AU - Alonzo, Todd A
AU - Stirewalt, Derek
AU - Othus, Megan
AU - Duployez, Nicolas
AU - Sonneveld, Edwin
AU - Abrahamsson, Jonas
AU - Fogelstrand, Linda
AU - von Neuhoff, Nils
AU - Hasle, Henrik
AU - Reinhardt, Dirk
AU - Meshinchi, Soheil
AU - Locatelli, Franco
AU - Pigazzi, Martina
PY - 2025/3/10
Y1 - 2025/3/10
N2 - PURPOSE: Several genomic subsets of
NPM1 mutations with varying sequences (type A, B, D, etc) have been identified. Despite molecular heterogeneity,
NPM1 mutations cumulatively portend a more favorable outcome, but biology and prognostic implications of different genomic subsets have not been extensively studied. In this multicentric study, we investigated the impact of
NPM1 genotypes on patient's outcomes and interrogated the underlying biology of the different subtypes.
MATERIALS AND METHODS: Of more than 4,000 patients enrolled in multiple pediatric cooperative (AIEOP, BFM, ELAM02, NOPHO, DCOG, and COG trials), or adult (SWOG) trials, 348 pediatric and 75 adult AML patients with known
NPM1 genotype and available outcome were selected for this study. Diverse
NPM1 variants were correlated with the probabilities of overall survival (OS) and event-free survival. Nuclear localization and translational efficiency of the
NPM1 variants was studied.
RESULTS: Evaluation of clinical outcome on the basis of
NPM1 genotypes showed that patients with type A, B, and other rare variants had similarly favorable outcomes, whereas those with type D had a significantly worse outcome (OS of 63% for type D
v 86% for type non-D,
P = .005). Multivariate analysis confirmed type D as an independent prognostic factor associated with inferior OS (hazard ratio, 3;
P = .005). In vitro, we demonstrated that in type D versus type A synonymous variants, codon optimality plays major roles in determining gene expression levels, and translation efficiency, which resulted in a more expressed
NPM1-D mRNA and protein, mediating peculiar mitochondrial gene expression.
CONCLUSION: The evaluation of specific
NPM1 genotypes identified AML patients with type D mutations being significantly associated with inferior outcomes, suggesting a reclassification of D cases to higher-risk groups.
AB - PURPOSE: Several genomic subsets of
NPM1 mutations with varying sequences (type A, B, D, etc) have been identified. Despite molecular heterogeneity,
NPM1 mutations cumulatively portend a more favorable outcome, but biology and prognostic implications of different genomic subsets have not been extensively studied. In this multicentric study, we investigated the impact of
NPM1 genotypes on patient's outcomes and interrogated the underlying biology of the different subtypes.
MATERIALS AND METHODS: Of more than 4,000 patients enrolled in multiple pediatric cooperative (AIEOP, BFM, ELAM02, NOPHO, DCOG, and COG trials), or adult (SWOG) trials, 348 pediatric and 75 adult AML patients with known
NPM1 genotype and available outcome were selected for this study. Diverse
NPM1 variants were correlated with the probabilities of overall survival (OS) and event-free survival. Nuclear localization and translational efficiency of the
NPM1 variants was studied.
RESULTS: Evaluation of clinical outcome on the basis of
NPM1 genotypes showed that patients with type A, B, and other rare variants had similarly favorable outcomes, whereas those with type D had a significantly worse outcome (OS of 63% for type D
v 86% for type non-D,
P = .005). Multivariate analysis confirmed type D as an independent prognostic factor associated with inferior OS (hazard ratio, 3;
P = .005). In vitro, we demonstrated that in type D versus type A synonymous variants, codon optimality plays major roles in determining gene expression levels, and translation efficiency, which resulted in a more expressed
NPM1-D mRNA and protein, mediating peculiar mitochondrial gene expression.
CONCLUSION: The evaluation of specific
NPM1 genotypes identified AML patients with type D mutations being significantly associated with inferior outcomes, suggesting a reclassification of D cases to higher-risk groups.
UR - http://www.scopus.com/inward/record.url?scp=86000672919&partnerID=8YFLogxK
U2 - 10.1200/JCO-24-01715
DO - 10.1200/JCO-24-01715
M3 - Journal article
C2 - 39621969
SN - 0732-183X
VL - 43
SP - 972
EP - 984
JO - Journal of clinical oncology : official journal of the American Society of Clinical Oncology
JF - Journal of clinical oncology : official journal of the American Society of Clinical Oncology
IS - 8
ER -