BCR-ABL1 alters SDF-1alpha-mediated adhesive responses through the beta2 integrin LFA-1 in leukemia cells.
Stromal-derived factor-1 (SDF-1) and its receptor, CXCR4, are essential for normal hematopoietic progenitor cell movement and adherence within the bone marrow microenvironment. In leukemia, the BCR-ABL1 oncoprotein inhibits SDF-1-dependent cell trafficking within the bone marrow through a mechanism that is not fully understood. Here, we report that BCR-ABL1 in malignant cells constitutively increases expression of activation-dependent epitopes of the beta(2) integrin LFA-1. This is associated with the complete loss of responsiveness of LFA-1 to SDF-1-induced "inside-out" signaling involving CXCR4 and Lyn, leading to aberrant adhesive responses. These data provide a novel, LFA-1-mediated mechanism whereby BCR-ABL1 inhibits SDF-1 action in malignant progenitors.
Chen
Ying-Yu
YY
Divisions of Hematology and Oncology, University of Pennsylvania School of Medicine, Philadelphia, USA.
Malik
Mobeen
M
Tomkowicz
Brian E
BE
Collman
Ronald G
RG
Ptasznik
Andrzej
A
D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000502:physiology*; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D006801:Humans; D007938:Leukemia / Q000473:pathology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism
D054377:Chemokine CXCL12; D016169:Lymphocyte Function-Associated Antigen-1; D019718:Receptors, CXCR4; D016044:Fusion Proteins, bcr-abl; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases