Details

Autor(en) / Beteiligte

• Burchert, Andreas
• Wang, Ying
• Brendel, Cornelia
• Erben, Philipp
• Manley, Paul W.
• Hochhaus, Andreas
• Cai, Dali
• Neubauer, Andreas

Titel

Adaptive Autocrine 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

Ist Teil von

• Blood, 2006-11, Vol.108 (11), p.2187-2187

Ort / Verlag

Elsevier Inc

Erscheinungsjahr

2006

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Overcoming 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 imatinib mesylate (IM, Gleevec™) 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-naïve 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). In a cell based resistance induction assay, GM-CSF enabled the evolution of IM- and NI-resistant colonies. When analysing GM-CSF expression in over 120 patient samples of first diagnosis CML patients and resistant patient, elevated mRNA and protein levels of GM-CSF were detected exclusively 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, this suggests that adaptive autocrine secretion of GM-CSF and cytokines in general may be a novel IM and NI resistance mechanism, which may also contribute to CML-persistence. GM-CSF protects CML-progenitors via a BCR/ABL-independent 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.