Abstract
The basis for persistence of leukemic stem cells in the bone marrow microenvironment remains poorly understood. We present evidence that signaling cross-talk between α4 integrin and Abelson interactor-1 (Abi-1) is involved in the acquisition of an anchorage-dependent phenotype and drug resistance in Bcr-Abl-positive leukemia cells. Comparison of Abi-1 (ABI-1) and α4 integrin (ITGA4) gene expression in relapsing Bcr-Abl-positive CD34+progenitor cells demonstrated a reduction in Abi-1 and an increase in α4 integrin mRNA in the absence of Bcr-Abl mutations. This inverse correlation between Abi-1 and α4 integrin expression, as well as linkage to elevated phospho-Akt and phospho-Erk signaling, was confirmed in imatinib mesylate -resistant leukemic cells. These results indicate that the α4-Abi-1 signaling pathway may mediate acquisition of the drug-resistant phenotype of leukemic cells.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics*
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Animals
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Antigens, CD34 / metabolism
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Cell Adhesion / drug effects
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Cell Adhesion / genetics
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Cell Line, Transformed
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Cell Proliferation / drug effects
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Cytoskeletal Proteins / genetics*
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Drug Resistance, Neoplasm / genetics*
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Fusion Proteins, bcr-abl / genetics*
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Gene Expression Regulation, Leukemic / drug effects
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Humans
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Integrin alpha4 / metabolism
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K562 Cells
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / genetics
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Mice
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Proteasome Endopeptidase Complex / metabolism
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Tumor Microenvironment / drug effects*
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Vascular Cell Adhesion Molecule-1 / metabolism
Substances
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ABI1 protein, human
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Adaptor Proteins, Signal Transducing
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Antigens, CD34
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Cytoskeletal Proteins
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Vascular Cell Adhesion Molecule-1
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Integrin alpha4
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Fusion Proteins, bcr-abl
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Proteasome Endopeptidase Complex