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

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

Author information

1
Clinical and Experimental Onco-Hematology Unit, CRO Aviano National Cancer Institute, Aviano, Italy.
2
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
3
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
4
Mayo Clinic College of Medicine, Rochester, MN.
5
Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases, and Rheumatology, Oncologic Center, Paracelsus Medical University, Salzburg, Austria.
6
Cancer Cluster Salzburg, Salzburg Cancer Research Institute-Laboratory for Immunological and Molecular Cancer Research, Salzburg, Austria.
7
Division of Hematology, S. Eugenio Hospital and University of Tor Vergata, Rome, Italy.
8
Clinica Ematologica, Centro Trapianti e Terapie Cellulari "Carlo Melzi" DISM, Azienda Ospedaliera Universitaria S. Maria Misericordia, Udine, Italy.
9
Division of Hematology, Ferrarotto Hospital, Catania, Italy.
10
Department of Internal Medicine and Hematology, Maggiore General Hospital, University of Trieste, Trieste, Italy.
11
Department of Pathology and Cancer Center, University of New Mexico, Albuquerque, NM.
12
Clinical and Experimental Onco-Hematology Unit, CRO Aviano National Cancer Institute, Aviano, Italy vgattei@cro.it.
13
Clinical and Experimental Onco-Hematology Unit, CRO Aviano National Cancer Institute, Aviano, Italy zucchetto.soecs@cro.it.

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.

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