Low expression of Abelson interactor-1 is linked to acquired drug resistance in Bcr-Abl-induced leukemia.
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.
Signal Transduction Laboratory, NIH Center of Biomedical Excellence (COBRE) for Stem Cell Biology, Roger Williams Medical Center, Boston University School of Medicine, Providence, RI, USA.
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Chorzalska
Signal Transduction Laboratory, NIH Center of Biomedical Excellence (COBRE) for Stem Cell Biology, Roger Williams Medical Center, Boston University School of Medicine, Providence, RI, USA.
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Salloum
Signal Transduction Laboratory, NIH Center of Biomedical Excellence (COBRE) for Stem Cell Biology, Roger Williams Medical Center, Boston University School of Medicine, Providence, RI, USA.
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Shafqat
Signal Transduction Laboratory, NIH Center of Biomedical Excellence (COBRE) for Stem Cell Biology, Roger Williams Medical Center, Boston University School of Medicine, Providence, RI, USA.
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Khan
Signal Transduction Laboratory, NIH Center of Biomedical Excellence (COBRE) for Stem Cell Biology, Roger Williams Medical Center, Boston University School of Medicine, Providence, RI, USA.
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Marjon
Hematopathology Laboratories at Rhode Island Hospital and Miriam Hospital, Providence, RI, USA.
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Treaba
Genomics Core Facility, Brown University, Providence, RI, USA.
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Schorl
Flow Cytometry and Cell Sorting Core Facility, NIH Center of Biomedical Excellence (COBRE) for Stem Cell Biology, Roger Williams Medical Center, Providence, RI, USA.
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Morgan
Cytogenetics, Quest Diagnostics Nichols Institute, Chantilly, VA, USA.
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Bryke
1] Department of Dermatology, Roger Williams Medical Center, Boston University School of Medicine, Providence, RI, USA [2] Departments of Dermatology and Biochemistry, Boston University School of Medicine, Boston, MA, USA.
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Falanga
Cardiovascular Lab, Department of Surgery, Roger Williams Medical Center, Boston University School of Medicine, Providence, RI, USA.
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Zhao
Division of Hematology/Oncology, Rhode Island Hospital, Brown University Warren Alpert School of Medicine, Providence, RI, USA.
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Reagan
Division of Hematology/Oncology, Rhode Island Hospital, Brown University Warren Alpert School of Medicine, Providence, RI, USA.
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Winer
Memorial Hospital of Rhode Island, Brown University Warren Alpert School of Medicine, Pawtucket, RI, USA.
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Olszewski
Adult Blood and Marrow Transplantation, Spectrum Health, Michigan State University, Grand Rapids, MI, USA.
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Al-Homsi
Department of Pathology, Roger Williams Medical Center, Boston University School of Medicine, Providence, RI, USA.
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Kouttab
Signal Transduction Laboratory, NIH Center of Biomedical Excellence (COBRE) for Stem Cell Biology, Roger Williams Medical Center, Boston University School of Medicine, Providence, RI, USA.
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Dubielecka
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D039441:Integrin alpha4 / Q000378:metabolism; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059016:Tumor Microenvironment / Q000187:drug effects*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
C513733:ABI1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D018952:Antigens, CD34; D003598:Cytoskeletal Proteins; D019010:Vascular Cell Adhesion Molecule-1; D039441:Integrin alpha4; D016044:Fusion Proteins, bcr-abl; D046988:Proteasome Endopeptidase Complex