Role of abnormal integrin-cytoskeletal interactions in impaired β1 integrin function in chronic myelogenous leukemia hematopoietic progenitors

Academic Article

Abstract

  • Abnormal circulation and unregulated proliferation of chronic myelogenous leukemia (CML) progenitors is related, at least in part, to BCR/ABL induced abnormalities in β1 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 β1 integrin- cytoskeletal interactions were present in primary CML progenitors and contributed to defective integrin function. β1 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 β1 integrins resulted in their redistribution into caps via a process requiring receptor- cytoskeletal interactions. CML CD34+ cells demonstrated significantly impaired β1 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 M07e(BCR/ABL) cells also demonstrated increased actin polymerization and altered actin cytoskeletal organization. Further studies suggested that impaired β1 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 α, which restores integrin-mediated adhesion and signaling in CML progenitors, also enhanced integrin capping in CD34+ cells. These studies suggest that p210(BCR/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.
  • Published In

    Digital Object Identifier (doi)

    Author List

  • Bhatia R; Munthe HA; Verfaillie CM
  • Start Page

  • 1384
  • End Page

  • 1396
  • Volume

  • 27
  • Issue

  • 9