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Chronic Lymphocytic Leukemia

The CD49d/CD29 complex is physically and functionally associated with CD38 in B-cell chronic lymphocytic leukemia cells

Leukemia volume 26, pages 1301–1312 (2012)Cite this article

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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.

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Acknowledgements

This study is supported in part by: the Ministero della Salute (Ricerca Finalizzata IRCCS, ‘Alleanza Contro il Cancro’, Rete Nazionale Bio-Informatica Oncologica/RN-BIO and ‘Giovani Ricercatori’ project, grant GR-2008-1138053), Rome, Italy; the Ministero dell’Istruzione (Bando FIRB Giovani 2008, grant # RBFR08ATLH and Bando PRIN 2009, LMEEEH_002), Rome, Italy; the Associazione Italiana contro le Leucemie, linfomi e mielomi (AIL), Venezia Section, Pramaggiore (VE) Group; the Associazione Italiana Ricerca Cancro (AIRC, Investigator Grant IG-8701 and IG-8590; MFAG 10327; Special Program Molecular Clinical Oncology, 5 × 1000, N. 10007 and N. 9980, 2010/15), the Milan, Italy; ‘5 × 1000 program’ of the Centro di Riferimento Oncologico, Aviano, Italy; Ricerca Scientifica Applicata, Regione Friuli Venezia Giulia, (‘Linfonet’ Project), Trieste, Italy and the Human Genetics Foundation, Turin, Italy. The Fondazione Internazionale di Ricerca in Medicina Sperimentale (Turin, Italy) provided valuable administrative assistance. We thank Drs Francesca Cottino and Katiuscia Gizzi for excellent technical assistance.

Author information

Author notes

  1. A Zucchetto and T Vaisitti: Co-first authors.

  2. S Deaglio and V Gattei: Co-last authors.

Authors and Affiliations

  1. Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano, Italy

    A Zucchetto, D Benedetti, E Tissino, R Bomben, M Dal Bo & V Gattei

  2. Department of Genetics, Human Genetics Foundation, Biology and Biochemistry, University of Turin, Turin, Italy

    T Vaisitti & S Deaglio

  3. Department of Morphology and Embryology, Signal Transduction Unit, Section of Human Anatomy, University of Ferrara, Ferrara, Italy

    V Bertagnolo

  4. Department of Clinical and Experimental Medicine and IRCAD, Division of Hematology, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy

    D Rossi & G Gaidano

  5. Division of Hematology, S.Eugenio Hospital and University of Tor Vergata, Rome, Italy

    M I Del Principe & G Del Poeta

  6. Division of Hematology, Ferrarotto Hospital, University of Catania, Catania, Italy

    A Gorgone

  7. Department of Internal Medicine and Hematology, Maggiore General Hospital, University of Trieste, Trieste, Italy

    G Pozzato

  8. Department of Genetics, Laboratory of Immunogenetics, Biology and Biochemistry, University of Turin, Turin, Italy

    F Malavasi

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  1. A Zucchetto
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Correspondence to V Gattei.

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Zucchetto, A., Vaisitti, T., Benedetti, D. et al. The CD49d/CD29 complex is physically and functionally associated with CD38 in B-cell chronic lymphocytic leukemia cells. Leukemia 26, 1301–1312 (2012). https://doi.org/10.1038/leu.2011.369

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