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

J Exp Med. 2018 Feb 5;215(2):681-697. doi: 10.1084/jem.20171288. Epub 2018 Jan 4.

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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase / antagonists & inhibitors
  • Agammaglobulinaemia Tyrosine Kinase / metabolism
  • Cell Adhesion / drug effects
  • Humans
  • Immunoglobulin M / metabolism
  • Integrin alpha4beta1 / metabolism*
  • Kaplan-Meier Estimate
  • Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
  • Lymph Nodes / drug effects
  • Lymph Nodes / metabolism
  • Lymph Nodes / pathology
  • Lymphocytosis / metabolism
  • Lymphocytosis / pathology
  • Multivariate Analysis
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Progression-Free Survival
  • Proportional Hazards Models
  • Protein Kinase Inhibitors / pharmacology
  • Pyrazoles / pharmacology
  • Pyrazoles / therapeutic use*
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use*
  • Receptors, Antigen, B-Cell / metabolism

Substances

  • Immunoglobulin M
  • Integrin alpha4beta1
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • Receptors, Antigen, B-Cell
  • ibrutinib
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human