Granulocyte-macrophage colony-stimulating factor (GM-CSF) induces antiapoptotic and proapoptotic signals in acute myeloid leukemia.

Abstract	High levels of cytokines are associated with a poor prognosis in acute myeloid leukemia (AML). However, cytokines may induce, on one hand, survival factor expression and cell proliferation and, on the other hand, expression of inhibitory signals such as up-regulation of suppressors of cytokine signaling (SOCS) and induce apoptotic cell death. Because blasts from patients with AML express high procaspase protein levels, we asked whether granulocyte-macrophage colony-stimulating factor (GM-CSF) enhances procaspase protein production in AML cells. In the GM-CSF-responsive OCIM2 AML cell line, GM-CSF induced signal transducer and activator of transcription 5 (Stat 5) phosphorylation, up-regulated cyclin D2, and stimulated cell cycle progression. Concurrently, GM-CSF stimulated expression of SOCS-2 and -3 and of procaspases 2 and 3 and induced caspase 3 activation, poly(ADP[adenosine 5'-diphosphate]-ribose) polymerase (PARP) cleavage, and apoptotic cell death. The Janus kinase (Jak)-Stat inhibitor AG490 abrogated GM-CSF-induced expression of procaspase 3 and activation of caspase 3. Under the same conditions GM-CSF up-regulated production of BAX as well as Bcl-2, Bcl-XL, survivin, and XIAP. GM-CSF also increased procaspase 3 protein levels in OCI/AML3 and Mo7e cells, suggesting that this phenomenon is not restricted to a single leukemia cell line. Our data suggest that GM-CSF exerts a dual effect: it stimulates cell division but contemporaneously up-regulates Jak-Stat-dependent proapoptotic proteins. Up-regulation of procaspase levels in AML is thus a beacon for an ongoing growth-stimulatory signal.
Authors	Stefan Faderl, David Harris, Quin Van, Hagop M Kantarjian, Moshe Talpaz, Zeev Estrov
Journal	Blood (Blood) Vol. 102 Issue 2 Pg. 630-7 (Jul 15 2003) ISSN: 0006-4971 [Print] United States
PMID	12663443 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References	BAX protein, human BCL2L1 protein, human BIRC5 protein, human DNA-Binding Proteins Enzyme Inhibitors Enzyme Precursors Inhibitor of Apoptosis Proteins Microtubule-Associated Proteins Neoplasm Proteins Proteins Proto-Oncogene Proteins Proto-Oncogene Proteins c-bcl-2 Recombinant Proteins Repressor Proteins SOCS2 protein, human SOCS3 protein, human Suppressor of Cytokine Signaling 3 Protein Suppressor of Cytokine Signaling Proteins Survivin Trans-Activators Transcription Factors Tyrphostins X-Linked Inhibitor of Apoptosis Protein XIAP protein, human alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide bcl-2-Associated X Protein bcl-X Protein Granulocyte-Macrophage Colony-Stimulating Factor Poly(ADP-ribose) Polymerases Caspases
Topics	Acute Disease Apoptosis (drug effects) Caspases (biosynthesis, genetics) Cell Division (drug effects) DNA-Binding Proteins Enzyme Induction (drug effects) Enzyme Inhibitors (pharmacology) Enzyme Precursors (biosynthesis, genetics) Gene Expression Regulation, Neoplastic (drug effects) Genes, bcl-2 Granulocyte-Macrophage Colony-Stimulating Factor (pharmacology) Humans Inhibitor of Apoptosis Proteins Leukemia, Erythroblastic, Acute (pathology) Leukemia, Myeloid (pathology) Microtubule-Associated Proteins (biosynthesis, genetics) Neoplasm Proteins (biosynthesis, genetics) Poly(ADP-ribose) Polymerases (metabolism) Protein Biosynthesis Proteins (genetics) Proto-Oncogene Proteins (biosynthesis, genetics) Proto-Oncogene Proteins c-bcl-2 (biosynthesis, genetics) Recombinant Proteins (pharmacology) Repressor Proteins Signal Transduction (drug effects) Suppressor of Cytokine Signaling 3 Protein Suppressor of Cytokine Signaling Proteins Survivin Trans-Activators Transcription Factors Tumor Cells, Cultured (cytology, drug effects) Tumor Stem Cell Assay Tyrphostins (pharmacology) X-Linked Inhibitor of Apoptosis Protein bcl-2-Associated X Protein bcl-X Protein

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