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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.
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NEOPLASIA
Adaptive secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) mediates imatinib and nilotinib resistance in BCR/ABL+ progenitors via JAK-2/STAT-5 pathway activation
Ying Wang1,
Dali Cai1,
Cornelia Brendel1,
Christine Barett1,
Philipp Erben2,
Paul W. Manley3,
Andreas Hochhaus2,
Andreas Neubauer1, and
Andreas Burchert1
1 Philipps Universität Gießen und Marburg, Standort Marburg, Klinik für Hämatologie, Onkologie und Immunologie, Marburg, Germany;
2 Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, III, Medizinische Klinik, Mannheim, Germany;
3 Novartis Institutes for Biomedical Research, Oncology, Novartis Pharma, Basel, Switzerland
Overcoming imatinib mesylate (IM) resistance and disease persistence in patients with chronic myeloid leukemia (CML) is of considerable importance to the issue of potential cure. Here we asked whether autocrine signaling contributes to survival of BCR/ABL+ cells in the presence of IM and nilotinib (NI; AMN107), 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 janus kinases 2 (JAK-2)/signal transducer and activator of transcription 5 (STAT-5) signaling pathway in GM-CSF receptor  receptor (CD116)–expressing cells, including primary CD34+/CD116+ GM progenitors (GMPs). 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 antiapoptotic 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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