The Journal of Experimental Medicine
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Published 2 September 2002. doi:10.1084/jem.20020519
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© Rockefeller University Press, 0022-1007/2002/9/667/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 5, September 2, 2002 667-678

Crosstalk Between BCR/ABL Oncoprotein and CXCR4 Signaling through a Src Family Kinase in Human Leukemia Cells

Andrzej Ptasznik1, Elzbieta Urbanowska1,2, Suneetha Chinta1, Melinda A. Costa1, Benjamin A. Katz1, Marisha A. Stanislaus1, Gokhan Demir1, Diana Linnekin3, Zhixing K. Pan4 and Alan M. Gewirtz1

1 Division of Hematology/Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
2 Department of Hematology/Oncology and Internal Medicine, Medical University of Warsaw, Warsaw 00-097, Poland
3 Basic Research Laboratory, Division of Basic Sciences, National Cancer Institute, Frederick, MD 21702
4 Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037

Address correspondence to Andrzej Ptasznik, Hematology/Oncology Division, University of Pennsylvania School of Medicine, BRB-2, Seventh Floor, Rm. 712, 421 Curie Boulevard, Philadelphia, PA 19104-6100. Phone: 215-573-4804; Fax: 215-573-7049. E-mail: andrzejp2{at}cs.com or Alan M. Gewirtz, Department of Medicine, University of Pennsylvania, 421 Curie Boulevard, Philadelphia, PA 19104-6100. Phone: 215-573-4804; Fax: 215-573-7049. E-mail: gewirtz{at}mail.med.upenn.edu

Stromal-derived factor (SDF)-1 and its G protein–coupled receptor, CXCR4, regulate stem/progenitor cell migration and retention in the marrow and are required for hematopoiesis. We show here an interaction between CXCR4 and the Src-related kinase, Lyn, in normal progenitors. We demonstrate that CXCR4-dependent stimulation of Lyn is associated with the activation of phosphatidylinositol 3-kinase (PI3-kinase). This chemokine signaling, which involves a Src-related kinase and PI3-kinase, appears to be a target for BCR/ABL, a fusion oncoprotein expressed only in leukemia cells. We show that the binding of phosphorylated BCR/ABL to Lyn results in the constitutive activation of Lyn and PI3-kinase, along with a total loss of responsiveness of these kinases to SDF-1 stimulation. Inhibition of BCR/ABL tyrosine kinase with STI571 restores Lyn responsiveness to SDF-1 signaling. Thus, BCR/ABL perturbs Lyn function through a tyrosine kinase-dependent mechanism. Accordingly, the blockade of Lyn tyrosine kinase inhibits both BCR/ABL-dependent and CXCR4-dependent cell movements. Our results demonstrate, for the first time, that Lyn-mediated pathological crosstalk exists between BCR/ABL and the CXCR4 pathway in leukemia cells, which disrupts chemokine signaling and chemotaxis, and increases the ability of immature cells to escape from the marrow. These results define a Src tyrosine kinases-dependent mechanism whereby BCR/ABL (and potentially other oncoproteins) dysregulates G protein–coupled receptor signaling and function of mammalian precursors.

Key Words: BCR/ABL • Src • chemokine receptors • leukemia • chemotaxis


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