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Blood, 15 April 2004, Vol. 103, No. 8, pp. 3167-3174. Prepublished online as a Blood First Edition Paper on December 11, 2003; DOI 10.1182/blood-2003-04-1271. This Article Full Text (PDF) All Versions of this Article: 2003-04-1271v1 103/8/3167    most recent 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 Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Chu, S. Articles by Bhatia, R. Search for Related Content PubMed PubMed Citation Articles by Chu, S. Articles by Bhatia, R. Related Collections Related Article in Blood Online Social Bookmarking                   What's this? Submitted April 24, 2003 Accepted December 3, 2003 BCR/ABL kinase inhibition by imatinib mesylate enhances MAP kinase activity in chronic myelogenous leukemia CD34+ cells Su Chu, Melissa Holtz, Mamta Gupta, and Ravi Bhatia* Divison of Hematology and BMT, City of Hope National Medical Center, Duarte, CA, USA * Corresponding author; email: rbhatia{at}coh.org. Chronic myelogenous leukemia (CML) results from malignant transformation of a primitive hematopoietic cell by the BCR/ABL oncogene. The BCR/ABL tyrosine kinase inhibitor imatinib mesylate is highly effective in inducing remissions in CML. However effects of imatinib on intracellular signaling in primary progenitor cells are not well described. We show that imatinib exposure resulted in a significant, dose-responsive reduction in BCR/ABL kinase activity in CML CD34+ cells. However, imatinib treatment resulted in an increase in activity of p42/44 MAPK, an important downstream effecter of BCR/ABL. Increased MAPK activity was growth factor dependent. Pharmacological inhibition of MAPK using MEK-1/2 inhibitors significantly reduced CML progenitor proliferation. Combined treatment with a MEK-1/2 inhibitor and imatinib significantly increased suppression of CML progenitors compared with either inhibitor alone. In contrast imatinib treatment resulted in a small reduction in AKT activity. Combined treatment with a PI-3 kinase inhibitor and imatinib significantly increased suppression of CML progenitor growth compared with either inhibitor alone. We conclude that inhibition of BCR/ABL kinase activity in CML progenitors by imatinib results in a growth factor dependent compensatory increase in MAPK activity, and in only partial inhibition of PI-3 kinase activity. These mechanisms may contribute to incomplete elimination of CML progenitors by imatinib. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Can we cure CML? 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