Expression profiling of a hemopoietic cell survival transcriptome implicates osteopontin as a functional prognostic factor in AML

Powell, Jason A., Thomas, Daniel, Barry, Emma F., Kok, Chung H., McClure, BJ, Tsykin, Anna, To, L. Bik, Brown, Anna, Lewis, Ian D., Herbert, Kirsten, Goodall, Gregory J., Speed, Terence P., Asou, Norio, Jacob, Bindya, Osato, Motomi, Haylock, Dylan N., Nilsson, Susan K., D'Andrea, Richard J., Lopez, Angel F. and Guthridge, Mark A. 2009, Expression profiling of a hemopoietic cell survival transcriptome implicates osteopontin as a functional prognostic factor in AML, Blood, vol. 114, no. 23, pp. 4859-4870, doi: 10.1182/blood-2009-02-204818.

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Title Expression profiling of a hemopoietic cell survival transcriptome implicates osteopontin as a functional prognostic factor in AML
Author(s) Powell, Jason A.
Thomas, Daniel
Barry, Emma F.
Kok, Chung H.
McClure, BJ
Tsykin, Anna
To, L. Bik
Brown, Anna
Lewis, Ian D.
Herbert, Kirsten
Goodall, Gregory J.
Speed, Terence P.
Asou, Norio
Jacob, Bindya
Osato, Motomi
Haylock, Dylan N.
Nilsson, Susan K.
D'Andrea, Richard J.
Lopez, Angel F.
Guthridge, Mark A.ORCID iD for Guthridge, Mark A. orcid.org/0000-0002-0536-3471
Journal name Blood
Volume number 114
Issue number 23
Start page 4859
End page 4870
Total pages 12
Publisher American Society of Hematology
Place of publication Washington, D.C.
Publication date 2009-11-26
ISSN 0006-4971
1528-0020
Keyword(s) Science & Technology
Life Sciences & Biomedicine
Hematology
ACUTE MYELOID-LEUKEMIA
ACUTE MYELOGENOUS LEUKEMIA
COLONY-STIMULATING FACTORS
STEM-CELLS
INDUCTION THERAPY
C-MYC
RECEPTOR
CANCER
ACTIVATION
APOPTOSIS
Summary Deregulated 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.
Language eng
DOI 10.1182/blood-2009-02-204818
Indigenous content off
Field of Research 1102 Cardiorespiratory Medicine and Haematology
1103 Clinical Sciences
1114 Paediatrics and Reproductive Medicine
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2009, American Society of Hematology
Persistent URL http://hdl.handle.net/10536/DRO/DU:30132381

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