IntroductionGenomewide analysis of diagnostic bone marrow samples from patients for whom therapy fails may provide insight into particular profiles of gene expression that determine outcome. Understanding the relationships of known biologic markers to outcome using genomic profiles should help develop rational targeted therapies.In acute myeloid leukemia (AML), mutations of the Fms-like tyrosine kinase 3 (FLT3) receptor are markers of poor outcomes. Several studies in children and adults suggested that FLT3 internal tandem duplication (FLT3-ITD) confers poor prognosis in AML. [1][2][3][4][5][6] The FLT3 receptor is a member of the class III receptor tyrosine kinase (RTK) family. 7,8 High FLT3 receptor expression has been reported in more than 60% of precursor B-cell acute lymphocytic leukemia and AML cases, 9-11 and it is the most frequently mutated RTK 2,4,6 in adult and childhood de novo AML. Most FLT3 mutations result in constitutive activation and autophosphorylation of the FLT3 receptor. This results in downstream activation of the signal transducer and activator of transcription 5 (STAT5), phosphatidylinositol 3 (PI-3) kinase, and Ras pathways. 6,[12][13][14][15][16][17][18][19][20][21][22][23] Activation of these pathways leads to enhanced proliferation and resistance to apoptosis. 24,25 There are 2 types of FLT3 receptor mutations that have been described: internal tandem duplications (ITDs) in the juxtamembrane region [26][27][28][29][30][31] and activation loop mutations (ALMs) in the tyrosine kinase domain. [32][33][34] The incidence of FLT3-ITD is 11% to 16% in children 3,5 and 20% or more in adults 2,35 ; whereas, the incidence of point mutations is 7% to 8% in adults and children. 6,35 In studies by Whitman et al 4 and Liang et al, 5 a higher ratio of ITD to wild-type (WT) allele had a strong correlation with poor outcome, whereas a lower ratio correlated with an outcome similar to a FLT3-WT receptor. Meshinchi et al 3 reported that FLT3-ITD correlated highly with refractoriness to induction therapy in the Children's Cancer Group study 2891. Zwaan et al 36 reported similar results after analyzing a larger set of samples from several Berlin-Frankfurt-Müenster and Dutch Childhood Leukemia Group studies. As with most biologic markers, FLT3-ITD and FLT3-ALM convey a high but not absolute risk of poor outcome.In this study, we used DNA microarray analysis to identify a pattern of gene expression associated with a high-risk of treatment failure in specimens with FLT3 mutations (FLT3-MUs) in childhoodAML patients. There are 2 genes included in this expression profile that are also predictive of outcome when analyzed separately and provide insight into a possible mechanism by which FLT3-MUs confer a poor prognosis. Patients, materials, and methods Arrays Childhood de novo acute myeloid leukemia specimensThe specimens used in this study were archived at the Children's Oncology Group AML cell bank from Pediatric Oncology Group (POG) study 9421. Institutional review board (IRB) approval was obtained for gen...

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