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Prepublished online as a Blood First Edition Paper on March 27, 2003; DOI 10.1182/blood-2002-06-1890.
Submitted June 28, 2002
Accepted March 10, 2003
Granulocyte-macrophage colony-stimulating factor (GM-CSF) induces antiapoptotic and proapoptotic signals in acute myeloid leukemia
Stefan Faderl, David Harris, Quin Van, Hagop M Kantarjian, Moshe Talpaz, and Zeev Estrov*
Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
Department of Bioimmunotherapy, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
* Corresponding author; email: zestrov{at}mdanderson.org.
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 upregulation 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 GM-CSF enhances procaspase protein production in AML cells. In the GM-CSF-responsive OCIM2 AML cell line, GM-CSF induced Stat 5 phosphorylation, upregulated 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-ribose) polymerase (PARP) cleavage, and apoptotic cell death. The JAK-STAT inhibitor AG490 abrogated GM-CSF-induced expression of procaspase 3 and activation of caspase 3. Under the same conditions GM-CSF upregulated 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 upregulates JAK-STAT-dependent proapoptotic proteins. Upregulation of procaspase levels in AML is thus a beacon for an ongoing growth-stimulatory signal.
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