Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia

Erika Tissino, Dania Benedetti, Sarah E.M. Herman, Elisa ten Hacken, Inhye E. Ahn, Kari G. Chaffee, Francesca Maria Rossi, Michele Dal Bo, Pietro Bulian, Riccardo Bomben, Elisabeth Bayer, Andrea Härzschel, Julia Christine Gutjahr, Massimiliano Postorino, Enrico Santinelli, Ayed Ayed, Francesco Zaja, Annalisa Chiarenza, Gabriele Pozzato, Alexandre ChigaevLarry A. Sklar, Jan A. Burger, Alessandra Ferrajoli, Tait D. Shanafelt, Adrian Wiestner, Giovanni Del Poeta, Tanja Nicole Hartmann, Valter Gattei, Antonella Zucchetto

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12 Scopus citations

Abstract

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, which antagonizes B cell receptor (BCR) signals, demonstrates remarkable clinical activity in chronic lymphocytic leukemia (CLL). The lymphocytosis experienced by most patients under ibrutinib has previously been attributed to inhibition of BTK-dependent integrin and chemokine cues operating to retain the tumor cells in nodal compartments. Here, we show that the VLA-4 integrin, as expressed by CD49d-positive CLL, can be inside-out activated upon BCR triggering, thus reinforcing the adhesive capacities of CLL cells. In vitro and in vivo ibrutinib treatment, although reducing the constitutive VLA-4 activation and cell adhesion, can be overcome by exogenous BCR triggering in a BTK-independent manner involving PI3K. Clinically, in three independent ibrutinib-treated CLL cohorts, CD49d expression identifies cases with reduced lymphocytosis and inferior nodal response and behaves as independent predictor of shorter progression- free survival, suggesting the retention of CD49d-expressing CLL cells in tissue sites via activated VLA-4. Evaluation of CD49d expression should be incorporated in the characterization of CLL undergoing therapy with BCR inhibitors.

Original languageEnglish (US)
Pages (from-to)681-697
Number of pages17
JournalJournal of Experimental Medicine
Volume215
Issue number2
DOIs
StatePublished - Feb 1 2018

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Tissino, E., Benedetti, D., Herman, S. E. M., ten Hacken, E., Ahn, I. E., Chaffee, K. G., Rossi, F. M., Bo, M. D., Bulian, P., Bomben, R., Bayer, E., Härzschel, A., Gutjahr, J. C., Postorino, M., Santinelli, E., Ayed, A., Zaja, F., Chiarenza, A., Pozzato, G., ... Zucchetto, A. (2018). Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia. Journal of Experimental Medicine, 215(2), 681-697. https://doi.org/10.1084/jem.20171288