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Autor(en) / Beteiligte

Titel

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

Ist Teil von

Ort / Verlag

United States: Rockefeller University Press

Erscheinungsjahr

2018

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

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.

Sprache: Englisch
Identifikatoren: ISSN: 0022-1007
eISSN: 1540-9538
DOI: 10.1084/jem.20171288
Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5789417

Format: –
Schlagworte: 1-Phosphatidylinositol 3-kinase, Agammaglobulinaemia Tyrosine Kinase - antagonists & inhibitors, Agammaglobulinaemia Tyrosine Kinase - metabolism, B-cell receptor, Bruton's tyrosine kinase, CD29 antigen, CD49d antigen, Cell activation, Cell adhesion, Cell adhesion & migration, Cell Adhesion - drug effects, Cell survival, Chronic lymphatic leukemia, Cues, Humans, Immunoglobulin M - metabolism, Integrin alpha4beta1 - metabolism, Kaplan-Meier Estimate, Leukemia, Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy, Lymph Nodes - drug effects, Lymph Nodes - metabolism, Lymph Nodes - pathology, Lymphatic leukemia, Lymphocyte receptors, Lymphocytes B, Lymphocytosis, Lymphocytosis - metabolism, Lymphocytosis - pathology, Multivariate Analysis, Patients, Phosphatidylinositol 3-Kinases - metabolism, Phosphoinositide-3 Kinase Inhibitors, Progression-Free Survival, Proportional Hazards Models, Protein Kinase Inhibitors - pharmacology, Protein-tyrosine kinase, Pyrazoles - pharmacology, Pyrazoles - therapeutic use, Pyrimidines - pharmacology, Pyrimidines - therapeutic use, Receptors, Antigen, B-Cell - metabolism, Tumor cells, Tyrosine, VLA-4 antigen

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