Crosstalk between BCR/ABL oncoprotein and CXCR4 signaling through a Src family kinase in human leukemia cells.
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.
Division of Hematology/Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6100, USA. andrzejp2@cs.com
Andrzej
A
Ptasznik
Elzbieta
E
Urbanowska
Suneetha
S
Chinta
Melinda A
MA
Costa
Benjamin A
BA
Katz
Marisha A
MA
Stanislaus
Gokhan
G
Demir
Diana
D
Linnekin
Zhixing K
ZK
Pan
Alan M
AM
Gewirtz
D000818:Animals; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism; D018922:HL-60 Cells; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D020239:Receptor Cross-Talk; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction; D019061:src-Family Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D019718:Receptors, CXCR4; D019869:Phosphatidylinositol 3-Kinases; D016044:Fusion Proteins, bcr-abl; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D019204:GTP-Binding Proteins
Non-programmatic