title: Role of abnormal integrin-cytoskeletal interactions in impaired beta1 integrin function in chronic myelogenous leukemia hematopoietic progenitors.
abstract: Abnormal circulation and unregulated proliferation of chronic myelogenous leukemia (CML) progenitors is related, at least in part, to BCR/ABL induced abnormalities in beta1 integrin-mediated adhesion and signaling. The BCR/ABL oncogene has several potential interactions with cytoskeletal elements that are important for normal integrin signaling. In the present study, we evaluated whether abnormalities in beta1 integrin-cytoskeletal interactions were present in primary CML progenitors and contributed to defective integrin function. beta1 integrin-cytoskeletal interactions were studied in CML and normal CD34+ primary hematopoietic progenitors as well as BCR/ABL-transfected or mock-transfected M07e cells. In normal CD34+ progenitors, antibody-mediated cross-linking of beta1 integrins resulted in their redistribution into caps via a process requiring receptor-cytoskeletal interactions. CML CD34+ cells demonstrated significantly impaired beta1 integrin capping. This defect was related to the presence of the BCR/ABL gene, because capping also was impaired in BCR/ABL-transfected M07e cells. Defective receptor capping was not seen for non-integrin receptors. In addition, CML CD34- and M07eBCR/ABL cells also demonstrated increased actin polymerization and altered actin cytoskeletal organization. Further studies suggested that impaired beta1 integrin capping and defective integrin-mediated adhesion and proliferation inhibition in CML cells were related to abnormally enhanced integrin-cytoskeletal association and restricted receptor mobility. Finally, interferon alpha, which restores integrin-mediated adhesion and signaling in CML progenitors, also enhanced integrin capping in CD34+ cells. These studies suggest that p210BCR/ABL induces abnormal association of integrin receptors with the cytoskeleton and restricted receptor mobility and provide new insights into mechanisms underlying abnormal integrin function in CML progenitors.
authors.affiliation: Department of Hematology and Bone Marrow Transplantation, City of Hope National Medical Center, Duarte, CA 91010, USA. rbhatia@smtplink.coh.org
authors.forename: R
authors.initials: R
authors.lastname: Bhatia
authors.forename: H A
authors.initials: HA
authors.lastname: Munthe
authors.forename: C M
authors.initials: CM
authors.lastname: Verfaillie
mesh_terms: D000199:Actins / Q000032:analysis; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division; D002462:Cell Membrane / Q000648:ultrastructure; D002478:Cells, Cultured; D015638:Cytochalasin D / Q000494:pharmacology; D003599:Cytoskeleton / Q000737:chemistry / Q000187:drug effects / Q000473:pathology*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000737:chemistry / Q000473:pathology*; D006801:Humans; D019012:Integrin beta1 / Q000502:physiology*; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000737:chemistry / Q000473:pathology*; D011940:Receptor Aggregation; D011994:Recombinant Proteins; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D000199:Actins; D019012:Integrin beta1; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D015638:Cytochalasin D; D016044:Fusion Proteins, bcr-abl