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.
Highlights
CD49d, the α chain of the CD49d/CD29 integrin heterodimer very late antigen 4 (VLA-4), expressed in ∼40% of chronic lymphocytic leukemia (CLL) cases, has emerged as one of the most relevant biological predictors of overall survival (OS) and progression-free survival (PFS) in CLL (Gattei et al, 2008; Shanafelt et al, 2008; Bulian et al, 2014)
By taking advantage of three different cohorts of in vivo ibrutinib-treated CLL and of a series of ibrutinib-naive primary CLL samples, we demonstrate that (1) the VLA-4 integrin can be activated upon B cell receptor (BCR) triggering in ibrutinib-exposed CLL cells, (2) CLL cases expressing CD49d usually fail to display the canonical ibrutinib-induced lymphocytosis and experience a lower nodal response, and (3) CD49d expression is consistently associated with shorter PFS in the context of ibrutinib-treated CLL
The virtual absence of nonresponder cases in this CLL cohort may be explained by the correlation of high CD49d expression with the presence of other negative prognostic factors, such an unmutated (UM) immunoglobulin heavy chain variable (IGHV) mutational status and TP53 disruption (Table S1), which have previously been shown to be associated with BCR responsiveness (Mockridge et al, 2007; Apollonio et al, 2013)
Summary
CD49d, the α chain of the CD49d/CD29 integrin heterodimer very late antigen 4 (VLA-4), expressed in ∼40% of chronic lymphocytic leukemia (CLL) cases, has emerged as one of the most relevant biological predictors of overall survival (OS) and progression-free survival (PFS) in CLL (Gattei et al, 2008; Shanafelt et al, 2008; Bulian et al, 2014). VLA-4 mediates both cell–cell and cell–matrix interactions in CLL-involved tissues by respectively binding to its ligands vascular cell adhesion molecule 1 (VCAM-1) and fibronectin (Ruoslahti, 1991; Hartmann et al, 2009). VLA-4, usually present on the cell surface of resting leukocytes in an inactive conformation, can be activated in response to different stimuli, becoming competent.
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