Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia. Academic Article uri icon

Overview

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.

authors

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

publication date

  • January 4, 2018

Research

keywords

  • Integrin alpha4beta1
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Pyrazoles
  • Pyrimidines

Identity

PubMed Central ID

  • PMC5789417

Scopus Document Identifier

  • 85041384091

Digital Object Identifier (DOI)

  • 10.1158/1078-0432.CCR-16-0050

PubMed ID

  • 29301866

Additional Document Info

volume

  • 215

issue

  • 2