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J. Biol. Chem., Vol. 279, Issue 24, 25345-25352, June 11, 2004

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Role of the p38 Mitogen-activated Protein Kinase Pathway in the Generation of the Effects of Imatinib Mesylate (STI571) in BCR-ABL-expressing Cells^*

Simrit Parmar, Efstratios Katsoulidis, Amit Verma, Yongzhong Li, Antonella Sassano, Lakhvir Lal, Beata Majchrzak, Farhad Ravandi¶, Martin S. Tallman, Eleanor N. Fish, and Leonidas C. Platanias||

From the Robert H. Lurie Comprehensive Cancer Center and Division of Hematology Oncology, Northwestern University Medical School, Chicago, Illinois 60611, the ^¶Section of Hematology-Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois 60607, and the Division of Cell & Molecular Biology, Toronto Research Institute, University Network and Department of Immunology, University of Toronto, Toronto, Ontario M5G 2M1, Canada

Imatinib mesylate (STI571), a specific inhibitor of the BCR-ABL tyrosine kinase, exhibits potent antileukemic effects in vitro and in vivo. Despite the well established role of STI571 in the treatment of chronic myelogenous leukemia, the precise mechanisms by which inhibition of BCR-ABL tyrosine kinase activity results in generation of antileukemic responses remain unknown. In the present study we provide evidence that treatment of CML-derived BCR-ABL-expressing leukemia cells with STI571 results in activation of the p38 mitogen-activated protein (MAP) kinase signaling pathway. Our data indicate that STI571 induces phosphorylation of the p38 and activation of its kinase domain, in KT-1 cells and other BCR-ABL-expressing cell lines. We also identify the kinases MAP kinase-activated protein kinase-2 and Msk1 as two downstream effectors of p38, activated during inhibition of BCR-ABL activity by STI571. Importantly, pharmacological inhibition of p38 reverses the growth inhibitory effects of STI571 on primary leukemic colony-forming unit granulocyte/macrophage progenitors from patients with CML. Altogether, our data establish that activation of the p38 MAP kinase signaling cascade plays an important role in the generation of the effects of STI571 on BCR-ABL-expressing cells. They also suggest that, in addition to activation of mitogenic pathways, BCR-ABL promotes leukemogenesis by suppressing the function of growth inhibitory signaling cascades.

Received for publication, January 20, 2004 , and in revised form, March 15, 2004.

^* This work was supported by National Institutes of Health Grants CA94079 and CA77816 (to L. C. P.), a merit review grant from the Department of Veterans Affairs (to L. C. P.), Grant DAMD 17-03-1-0254 from the Department of Defense (to L. C. P.), and Canadian Institutes of Health Research Grant MOP 15094 (to E. N. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School, 710 North Fairbanks St., Olson 8250, Chicago, IL 60611. Tel.: 312-503-4267; Fax: 312-908-1372; E-mail: l-platanias{at}northwestern.edu.

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