title: The CD49d/CD29 complex is physically and functionally associated with CD38 in B-cell chronic lymphocytic leukemia cells.
abstract: CD49d and CD38 are independent negative prognostic markers in chronic lymphocytic leukemia (CLL). Their associated expression marks a disease subset with a highly aggressive clinical course. Here, we demonstrate a constitutive physical association between the CD49d/CD29 integrin complex and CD38 in primary CLL cells and B-cell lines by (i) cocapping, (ii) coimmunoprecipitation and (iii) cell adhesion experiments using CD49d-specific substrates (vascular-cell adhesion molecule-1 or CS-1/H89 fibronectin fragments). The role of CD38 in CD49d-mediated cell adhesion was studied in CD49d(+)CD38(+) and CD49d(+)CD38(-) primary CLL cells, and confirmed using CD38 transfectants of the originally CD49d(+)CD38(-) CLL-derived cell line Mec-1. Results indicate that CD49d(+)CD38(+) cells adhered more efficiently onto CD49d-specific substrates than CD49d(+)CD38(-) cells (P < 0.001). Upon adhesion, CD49d(+)CD38(+) cells underwent distinctive changes in cell shape and morphology, with higher levels of phosphorylated Vav-1 than CD49d(+)CD38(-) cells (P = 0.0006) and a more complex distribution of F-actin to the adhesion sites. Lastly, adherent CD49d(+)CD38(+) cells were more resistant to serum-deprivation-induced (P < 0.001) and spontaneous (P = 0.03) apoptosis than the CD49d(+)CD38(-) counterpart. Altogether, our results point to a direct role for CD38 in enhancing CD49d-mediated adhesion processes in CLL, thus providing an explanation for the negative clinical impact exerted by these molecules when coexpressed in neoplastic cells.
authors.affiliation: Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Zucchetto
authors.forename: T
authors.initials: T
authors.lastname: Vaisitti
authors.forename: D
authors.initials: D
authors.lastname: Benedetti
authors.forename: E
authors.initials: E
authors.lastname: Tissino
authors.forename: V
authors.initials: V
authors.lastname: Bertagnolo
authors.forename: D
authors.initials: D
authors.lastname: Rossi
authors.forename: R
authors.initials: R
authors.lastname: Bomben
authors.forename: M
authors.initials: M
authors.lastname: Dal Bo
authors.forename: M I
authors.initials: MI
authors.lastname: Del Principe
authors.forename: A
authors.initials: A
authors.lastname: Gorgone
authors.forename: G
authors.initials: G
authors.lastname: Pozzato
authors.forename: G
authors.initials: G
authors.lastname: Gaidano
authors.forename: G
authors.initials: G
authors.lastname: Del Poeta
authors.forename: F
authors.initials: F
authors.lastname: Malavasi
authors.forename: S
authors.initials: S
authors.lastname: Deaglio
authors.forename: V
authors.initials: V
authors.lastname: Gattei
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism*; D000199:Actins / Q000378:metabolism; D017209:Apoptosis; D015153:Blotting, Western; D002448:Cell Adhesion / Q000502:physiology*; D049109:Cell Proliferation; D016895:Culture Media, Serum-Free; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D047468:Immunoprecipitation; D039441:Integrin alpha4 / Q000378:metabolism; D039041:Integrin alpha4beta1 / Q000378:metabolism*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism* / Q000473:pathology*; D021962:Membrane Microdomains / Q000378:metabolism; D010766:Phosphorylation; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000199:Actins; D016895:Culture Media, Serum-Free; D039041:Integrin alpha4beta1; D051567:Proto-Oncogene Proteins c-vav; C496618:VAV1 protein, human; D039441:Integrin alpha4; D051997:ADP-ribosyl Cyclase 1