Abstract
AbstractDeregulated cell survival programs are a classic hallmark of cancer. We have previously identified a serine residue (Ser585) in the βc subunit of the granulocyte-macrophage colony-stimulating factor receptor that selectively and independently promotes cell survival. We now show that Ser585 phosphorylation is constitutive in 20 (87%) of 23 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 βc Ser585-regulated transcriptome. Pathway analysis defines a gene network enriched for PI3-kinase target genes and 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 shown by siRNA-mediated knockdown of OPN expression that induces cell death 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 overall patient survival in normal karyotype AML (n = 60; HR = 2.2; P = .01). These results delineate a novel cytokine-regulated Ser585/PI3-kinase signaling network that is deregulated in AML and identify OPN as a potential prognostic and therapeutic target.
Highlights
Many hemopoietic cytokines are potent regulators of both cell survival and proliferation
We have previously shown in preliminary studies that the phospho-Tyr577/phospho-Ser[585] binary switch may be subject to deregulation in at least some patients with acute myeloid leukemia (AML).[12]
For the OPN expression studies, bone marrow aspirates of 95 consecutive patients diagnosed with AML between 1998 and 2008 at Royal Adelaide Hospital (RAH) Australia were obtained after informed consent according to institutional guidelines in keeping with the Declaration of Helsinki, and studies were approved by the RAH Human Ethics Committee
Summary
Many hemopoietic cytokines are potent regulators of both cell survival and proliferation. Segregating the cytokine-mediated signals that promote hemopoietic cell survival from those that regulate proliferation has important biologic advantages in that it enforces at least 2 obligate steps for cellular transformation and leukemogenesis: one in which deregulated cell proliferation programs are activated and the other in which deregulated survival signals override cell death programs
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