This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Konig, H. Articles by Bhatia, R. Search for Related Content PubMed PubMed Citation Articles by Konig, H. Articles by Bhatia, R.

Effects of Dasatinib on Src Kinase Activity and Downstream Intracellular Signaling in Primitive Chronic Myelogenous Leukemia Hematopoietic Cells

¹ Department of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center and ² Division of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, California; and ³ Section of Experimental Haematology, Cancer Division, University of Glasgow, Scotland, United Kingdom

Requests for reprints: Ravi Bhatia, Department of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA 91010. Phone: 626-359-8111, ext. 62705; Fax: 626-301-8973; E-mail: rbhatia{at}coh.org.

Key Words: tyrosine kinase inhibitors • hematopoietic stem cells • cancer stem cells • apoptosis

Bcr-Abl tyrosine kinase inhibitors (TKI) are effective in inducing remissions in chronic myelogenous leukemia (CML) patients but do not eliminate primitive CML hematopoietic cells. There is a need to identify mechanisms that contribute to retention of CML progenitors. Src family tyrosine kinases have been identified as potential mediators of Bcr-Abl–induced leukemogenesis. Dasatinib (BMS-354825) is a potent dual Abl/Src kinase inhibitor approved for clinical use in CML patients. We evaluated Src activity in primitive human CML progenitors from different stages of disease and investigated effects of Dasatinib on Src activity and downstream signaling pathways. P-Src expression was increased in CD34⁺ cells and CD34⁺CD38^– cells in all phases of CML. Dasatinib showed potent Src inhibitory activity in CML progenitors, inhibiting both Bcr-Abl–dependent and –independent Src activity. In contrast, Imatinib inhibited only Bcr-Abl–dependent Src activity. Dasatinib inhibited P–mitogen-activated protein kinase (MAPK), P-Akt, and P-STAT5 levels in CML progenitors in the absence of growth factors but not in the presence of growth factors. A marked increase in P-MAPK levels seen in the presence of growth factors with Imatinib was much less prominent with Dasatinib. Dasatinib significantly suppressed CML colony-forming cells and long-term culture-initiating cells but did not significantly alter the level of apoptosis-regulating proteins in CML CD34+ cells. Our results indicate that Dasatinib, in addition to potent anti–Bcr-Abl kinase activity, effectively inhibits Src kinase activity and downstream signaling pathways in CML progenitors but does not induce a strong proapoptotic response. These observations argue against a prominent role for Src kinases in persistence of primitive CML cells in TKI-treated patients. [Cancer Res 2008;68(23):9624–33]

This article has been cited by other articles:

				Z. Wu, P.-C. Chang, J. C. Yang, C.-Y. Chu, L.-Y. Wang, N.-T. Chen, A.-H. Ma, S. J. Desai, S. H. Lo, C. P. Evans, et al. Autophagy Blockade Sensitizes Prostate Cancer Cells towards Src Family Kinase Inhibitors Genes & Cancer, January 1, 2010; 1(1): 40 - 49. [Abstract] [Full Text] [PDF]

				D. Milojkovic and J. Apperley Mechanisms of Resistance to Imatinib and Second-Generation Tyrosine Inhibitors in Chronic Myeloid Leukemia Clin. Cancer Res., December 15, 2009; 15(24): 7519 - 7527. [Abstract] [Full Text] [PDF]