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Blood, 15 February 2008, Vol. 111, No. 4, pp. 2329-2338.
Prepublished online as a Blood First Edition Paper on December 4, 2007; DOI 10.1182/blood-2007-05-092056.
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Submitted May 25, 2007
Accepted November 26, 2007
Effective and selective inhibition of chronic myeloid leukemia primitive hematopoietic progenitors by the dual Src/Abl kinase inhibitor SKI-606
Heiko Konig, Tessa L. Holyoake, and Ravi Bhatia*
Department of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA, United States
Section of Experimental Haematology, Cancer Division, University of Glasgow, Glasgow, United Kingdom
* Corresponding author; email: rbhatia{at}coh.org.
Imatinib mesylate is highly effective in the treatment of chronic myeloid leukemia (CML) but is less effective in eliminating CML stem cells. We investigated whether SKI-606, a potent Bcr-Abl and Src kinase inhibitor without anti-PDGF or c-Kit activity, could effectively target primitive CML progenitors. CML and normal progenitors were cultured with SKI-606 or Imatinib. SKI-606 effectively inhibited Bcr-Abl kinase activity in CML CD34+ cells and inhibited Src phosphorylation more potently than Imatinib. However, SKI-606 and Imatinib resulted in similar suppression of CML primitive and committed progenitor proliferation and growth in CFC and LTC-IC assays. Exposure to either agent alone or in combination resulted in only modest increase in apoptosis. Evaluation of downstream signaling pathways indicated that Akt and STAT5 activity were not changed but a delayed increase in MAPK activity was seen at high concentrations of SKI-606. SKI-606 inhibited normal progenitor proliferation to a lesser extent than Imatinib. We conclude that SKI-606 effectively inhibits Bcr-Abl and Src kinase activity and inhibits CML progenitor growth with relatively little effect on normal progenitors. However SKI-606 does not demonstrate increased ability to eliminate primitive CML progenitors by apoptosis compared to Imatinib, emphasizing the need for additional strategies besides Bcr-Abl kinase inhibition for curative therapy of CML.
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