title: An FLT3 gene-expression signature predicts clinical outcome in normal karyotype AML.
abstract: Acute myeloid leukemia with normal karyotype (NK-AML) represents a cytogenetic grouping with intermediate prognosis but substantial molecular and clinical heterogeneity. Within this subgroup, presence of FLT3 (FMS-like tyrosine kinase 3) internal tandem duplication (ITD) mutation predicts less favorable outcome. The goal of our study was to discover gene-expression patterns correlated with FLT3-ITD mutation and to evaluate the utility of a FLT3 signature for prognostication. DNA microarrays were used to profile gene expression in a training set of 65 NK-AML cases, and supervised analysis, using the Prediction Analysis of Microarrays method, was applied to build a gene expression-based predictor of FLT3-ITD mutation status. The optimal predictor, composed of 20 genes, was then evaluated by classifying expression profiles from an independent test set of 72 NK-AML cases. The predictor exhibited modest performance (73% sensitivity; 85% specificity) in classifying FLT3-ITD status. Remarkably, however, the signature outperformed FLT3-ITD mutation status in predicting clinical outcome. The signature may better define clinically relevant FLT3 signaling and/or alternative changes that phenocopy FLT3-ITD, whereas the signature genes provide a starting point to dissect these pathways. Our findings support the potential clinical utility of a gene expression-based measure of FLT3 pathway activation in AML.
authors.affiliation: Department of Internal Medicine III, University of Ulm, Ulm, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Bullinger
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
authors.forename: Raphael
authors.initials: R
authors.lastname: Kranz
authors.forename: Christoph
authors.initials: C
authors.lastname: Stirner
authors.forename: Stefan
authors.initials: S
authors.lastname: Fröhling
authors.forename: Claudia
authors.initials: C
authors.lastname: Scholl
authors.forename: Young H
authors.initials: YH
authors.lastname: Kim
authors.forename: Richard F
authors.initials: RF
authors.lastname: Schlenk
authors.forename: Robert
authors.initials: R
authors.lastname: Tibshirani
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Pollack
mesh_terms: D020869:Gene Expression Profiling; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000235:genetics; D011237:Predictive Value of Tests; D011379:Prognosis; D020080:Tandem Repeat Sequences; D016896:Treatment Outcome; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: D051941:fms-Like Tyrosine Kinase 3