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Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789417/ https://www.ncbi.nlm.nih.gov/pubmed/29301866 http://dx.doi.org/10.1084/jem.20171288 |
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author | 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 |
author_facet | 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 |
author_sort | Tissino, Erika |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5789417 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-57894172018-02-05 Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia 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 J Exp Med Research Articles 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. The Rockefeller University Press 2018-02-05 /pmc/articles/PMC5789417/ /pubmed/29301866 http://dx.doi.org/10.1084/jem.20171288 Text en © 2018 Tissino et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Articles 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 Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia |
title | Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia |
title_full | Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia |
title_fullStr | Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia |
title_full_unstemmed | Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia |
title_short | Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia |
title_sort | functional and clinical relevance of vla-4 (cd49d/cd29) in ibrutinib-treated chronic lymphocytic leukemia |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789417/ https://www.ncbi.nlm.nih.gov/pubmed/29301866 http://dx.doi.org/10.1084/jem.20171288 |
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