In acute myeloid leukemia (AML), cyotgenetics is used to stratify cases for appropriate risk-adapted therapy. The largest subset of patients, those with normal karyotype AML (NK-AML), comprises a heterogeneous group with intermediate prognosis. To improve outcome prediction for this group, we carried out gene-expression profiling of a set of 65 clinically-annotated NK-AML cases. In exploratory studies, an outcome predictor derived from semi-supervised analysis comprised genes mainly correlated with the presence of FLT3 (fms-related tyrosine kinase 3) internal tandem duplication (ITD) activating mutation, itself a prognostic factor. We therefore sought to directly define and characterize a gene-expression predictor of FLT3-ITD mutation status. Using a supervised analysis (Prediction Analysis of Microarrays), we identified an optimal 25-gene FLT3 signature, which in an independent set of 73 NK-AML cases was a significant predictor of clinical outcome, notably outperforming FLT3-ITD mutation status itself. We speculate that the signature identifies cases with alternative genetic or epigenetic changes that phenocopy FLT3-ITD, and the signature genes provide a starting point to dissect these pathways. Our findings underscore the prognostic relevance of FLT3-ITD in NK-AML, and indicate the potential clinical utility of a gene-expression based measure of clinically-relevant FLT3 pathway activation.

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