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

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 A. Guthridge

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

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 survivalonly 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 ofOPN 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.

LanguageEnglish
Pages4859-4870
Number of pages12
JournalBlood
Volume114
Issue number23
DOIs
Publication statusPublished - 26 Nov 2009

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Powell, Jason A. ; Thomas, Daniel ; Barry, Emma F. ; Kok, Chung H. ; McClure, Barbara J. ; 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, David N. ; Nilsson, Susan K. ; D'Andrea, Richard J. ; Lopez, Angel F. ; Guthridge, Mark A. / Expression profiling of a hemopoietic cell survival transcriptome implicates osteopontin as a functional prognostic factor in AML. In: Blood. 2009 ; Vol. 114, No. 23. pp. 4859-4870.
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title = "Expression profiling of a hemopoietic cell survival transcriptome implicates osteopontin as a functional prognostic factor in AML",
abstract = "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 survivalonly 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 ofOPN 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.",
author = "Powell, {Jason A.} and Daniel Thomas and Barry, {Emma F.} and Kok, {Chung H.} and McClure, {Barbara J.} and Anna Tsykin and To, {L. Bik} and Anna Brown and Lewis, {Ian D.} and Kirsten Herbert and Goodall, {Gregory J.} and Speed, {Terence P.} and Norio Asou and Bindya Jacob and Motomi Osato and Haylock, {David N.} and Nilsson, {Susan K.} and D'Andrea, {Richard J.} and Lopez, {Angel F.} and Guthridge, {Mark A.}",
year = "2009",
month = "11",
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Powell, JA, Thomas, D, Barry, EF, Kok, CH, McClure, BJ, Tsykin, A, To, LB, Brown, A, Lewis, ID, Herbert, K, Goodall, GJ, Speed, TP, Asou, N, Jacob, B, Osato, M, Haylock, DN, Nilsson, SK, D'Andrea, RJ, Lopez, AF & Guthridge, MA 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. https://doi.org/10.1182/blood-2009-02-204818

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, Barbara J.; 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, David N.; Nilsson, Susan K.; D'Andrea, Richard J.; Lopez, Angel F.; Guthridge, Mark A.

In: Blood, Vol. 114, No. 23, 26.11.2009, p. 4859-4870.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Expression profiling of a hemopoietic cell survival transcriptome implicates osteopontin as a functional prognostic factor in AML

AU - Powell, Jason A.

AU - Thomas, Daniel

AU - Barry, Emma F.

AU - Kok, Chung H.

AU - McClure, Barbara J.

AU - Tsykin, Anna

AU - To, L. Bik

AU - Brown, Anna

AU - Lewis, Ian D.

AU - Herbert, Kirsten

AU - Goodall, Gregory J.

AU - Speed, Terence P.

AU - Asou, Norio

AU - Jacob, Bindya

AU - Osato, Motomi

AU - Haylock, David N.

AU - Nilsson, Susan K.

AU - D'Andrea, Richard J.

AU - Lopez, Angel F.

AU - Guthridge, Mark A.

PY - 2009/11/26

Y1 - 2009/11/26

N2 - 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 survivalonly 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 ofOPN 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.

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