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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2018
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.
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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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