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

نویسندگان

  • 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 Chigaev
  • Larry A Sklar
  • Jan A Burger
  • Alessandra Ferrajoli
  • Tait D Shanafelt
  • Adrian Wiestner
  • Giovanni Del Poeta
  • Tanja Nicole Hartmann
  • Valter Gattei
  • Antonella Zucchetto
چکیده

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.

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عنوان ژورنال:

دوره 215  شماره 

صفحات  -

تاریخ انتشار 2018