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|Title:||Expression profiling of a hemopoietic cell survival transcriptome implicates osteopontin as a functional prognostic factor in AML|
|Citation:||Blood, 2009; 114(23):4859-4870|
|Publisher:||Amer Soc Hematology|
|Jason A. Powell, Daniel Thomas, Emma F. Barry, Chung H. Kok, Barbara J. McClure, Anna Tsykin, L. Bik To, Anna Brown, Ian D. Lewis, Kirsten Herbert, Gregory J. Goodall, Terence P. Speed, Norio Asou, Bindya Jacob, Motomi Osato, David N. Haylock, Susan K. Nilsson, Richard J. D'Andrea, Angel F. Lopez and Mark A. Guthridge|
|Abstract:||Deregulated cell survival programs are a classic hallmark of cancer. We have previously identified a serine residue (Ser585) in the betac 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 betac 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.|
|Keywords:||Hematopoietic Stem Cells; Tumor Cells, Cultured; Humans; Leukemia, Myeloid; Phosphoserine; Neoplasm Proteins; RNA, Small Interfering; RNA, Messenger; RNA, Neoplasm; Prognosis; Gene Expression Profiling; Signal Transduction; Cell Survival; Gene Expression Regulation, Leukemic; Adult; Aged; Middle Aged; Female; Male; Osteopontin; Cytokine Receptor Common beta Subunit; Gene Regulatory Networks; Neoplastic Stem Cells; Gene Knockdown Techniques; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors|
|Description:||© 2009 by The American Society of Hematology|
|Appears in Collections:||Medicine publications|
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