Deregulated cell survival programs are a classical hallmark of cancer. We have previously identified a serine residue (Ser585) in the betac subunit of the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor that selectively and independently promotes cell survival. We now show that Ser585 phosphorylation is constitutive in 20/23 (87 ) acute myeloid leukemia (AML) patient samples indicating that this survival-only pathway is frequently deregulated in leukemia. We performed a global expression screen to identify gene targets of this survival pathway and report a 138-gene betac Ser585-regulated transcriptome. Pathway analysis defines a gene network enriched for PI 3-kinase target genes as well as a cluster of genes involved in cancer and cell survival. We show that one such gene, osteopontin (OPN), is a functionally relevant target of the Ser585-survival pathway as demonstrated by siRNA-mediated knockdown of OPN expression which induces apoptosis in both AML blasts and CD34(+)CD38(-)CD123(+) leukemic progenitors. Increased expression of OPN at diagnosis is associated with poor prognosis with multivariate analysis indicating that it is an independent predictor of reduced overall patient survival in normal karyotype AML (n=60,HR=2.2,p=0.01). These results delineate a novel cytokine-regulated Ser585/PI3-kinase signalling network that is deregulated in AML and identify OPN as a potential prognostic and therapeutic target.