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Blood, 1 March 2007, Vol. 109, No. 5, pp. 2147-2155.
Prepublished online as a Blood First Edition Paper on November 7, 2006; DOI 10.1182/blood-2006-08-040022.
 Previous Article | Next Article 
Submitted August 7, 2006
Accepted October 9, 2006
Adaptive secretion of the Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) mediates Imatinib- and Nilotinib-resistance in BCR/ABL-positive progenitors via JAK-2/STAT-5 pathway activation
Ying Wang, Dali Cai, Cornelia Brendel, Christine Barett, Philipp Erben, Paul W. Manley, Andreas Hochhaus, Andreas Neubauer, and Andreas Burchert*
Philipps Universitaet Giessen und Marburg, Standort Marburg, Germany
Medizin Mannheim der Universitaet Heidelberg, Germany
Novartis Pharma AG, Switzerland
* Corresponding author; email: burchert{at}staff.uni-marburg.de.
Overcoming imatinib mesylate (IM, GleevecTM) resistance and disease persistence in chronic myeloid leukemia (CML) patients is of considerable importance to the issue of potential cure. Here we asked whether autocrine signaling contributes to survival of BCR/ABL positive cells in presence of IM and nilotinib (AMN107, NI), a novel more selective Abl inhibitor. Conditioned media (CM) of IM-resistant LAMA84-cell clones (R-CM) was found to substantially protect IM-naive LAMA cells and primary CML progenitors from IM- or NI-induced cell death. This was due to an increased secretion of the granulocyte-macrophage colony stimulating factor (GM-CSF) which was identified as the causative factor mediating IM resistance in R-CM. GM-CSF elicited IM and NI drug resistance via a BCR/ABL-independent activation of the JAK-2/STAT-5 signaling pathway in GM-CSF-receptor alpha receptor (CD116) expressing cells, including primary CD34,+/CD116+ GM-progenitors (GMP). Elevated mRNA and protein levels of GM-CSF were detected in IM-resistant patient samples, suggesting a contribution of GM-CSF secretion for IM and NI resistance in vivo. Importantly, inhibition of JAK-2 with AG490 abrogated GM-CSF-mediated STAT-5 phosphorylation and NI resistance in vitro.
Together, adaptive autocrine secretion of GM-CSF mediates BCR/ABL-independent IM and NI resistance via activation of the anti-apoptotic JAK-2/STAT-5 pathway. Inhibition of JAK-2 overcomes GM-CSF-induced IM and NI progenitor cell resistance providing a rationale for the application of JAK-2 inhibitors to eradicate residual disease in CML.
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