Gene expression patterns in response to IL-3 in human AML patient mononuclear cells

Aberrant activation of β-catenin is a common event in Acute Myeloid Leukemia (AML), and is recognized as an independent predictor of poor prognosis. Although increased β-catenin signaling in AML has been associated with AML1-ETO and PML-RARα translocation products, and activating mutations in the FLT3 receptor, it remains unclear which mechanisms activate β-catenin in AML more broadly. Here, we describe a novel link between interleukin-3 (IL-3) signaling and the regulation of β-catenin in myeloid transformation and AML. Using a murine model of HoxB8 and IL-3 cooperation we show that IL-3 modulates β-catenin protein levels, and Cre-induced deletion of β-catenin abolishes IL-3 dependent growth and colony formation. In the erythroleukemic cell line TF-1.8, we observed increased β-catenin protein levels and nuclear localization in response to IL-3, which correlated with transcriptional induction of β-catenin target genes. Furthermore, IL-3 promoted β-catenin accumulation in a subset of AML patient samples, and microarray gene expression analysis of these cells revealed induction of WNT/β-catenin and TCF4 transcriptional gene signatures in an IL-3 dependent manner. This study is the first to link β-catenin activation to IL-3 and suggests that targeting IL-3 signaling may be an effective approach for the inhibition of β-catenin activity in some patients with AML. AML patient samples (AML1-4) were cultured in the presence or absence of hIL-3 for 6 or 16h.