File(s) under permanent embargo
Expression profiling of a hemopoietic cell survival transcriptome implicates osteopontin as a functional prognostic factor in AML
journal contribution
posted on 2009-11-26, 00:00 authored by 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, Mark GuthridgeMark GuthridgeDeregulated 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.
History
Journal
BloodVolume
114Issue
23Pagination
4859 - 4870Publisher
American Society of HematologyLocation
Washington, D.C.Publisher DOI
ISSN
0006-4971eISSN
1528-0020Language
engPublication classification
C1 Refereed article in a scholarly journalCopyright notice
2009, American Society of HematologyUsage metrics
Categories
No categories selectedKeywords
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC