Expression profiling of a hemopoietic cell survival transcriptome implicates osteopontin as a functional prognostic factor in AML.
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.
Powell
Jason A
JA
Cell Growth and Differentiation Laboratory, Division of Human Immunology, Centre for Cancer Biology, SA Pathology, Frome Road, Adelaide, SA 5000, Australia.
Thomas
Daniel
D
Barry
Emma F
EF
Kok
Chung H
CH
McClure
Barbara J
BJ
Tsykin
Anna
A
To
L Bik
LB
Brown
Anna
A
Lewis
Ian D
ID
Herbert
Kirsten
K
Goodall
Gregory J
GJ
Speed
Terence P
TP
Asou
Norio
N
Jacob
Bindya
B
Osato
Motomi
M
Haylock
David N
DN
Nilsson
Susan K
SK
D'Andrea
Richard J
RJ
Lopez
Angel F
AF
Guthridge
Mark A
MA
D000328:Adult; D000368:Aged; D002470:Cell Survival; D053648:Cytokine Receptor Common beta Subunit / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D055785:Gene Knockdown Techniques; D053263:Gene Regulatory Networks; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053495:Osteopontin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010768:Phosphoserine / Q000378:metabolism; D011379:Prognosis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D053648:Cytokine Receptor Common beta Subunit; D009363:Neoplasm Proteins; D053495:Osteopontin; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010768:Phosphoserine; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; C115876:CSF2RB protein, human