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

Publication Date:
2018-02-10
Publisher:
Rockefeller University Press
Print ISSN:
0022-1007
Electronic ISSN:
1540-9538
Topics:
Medicine
Keywords:
Leukemia & Lymphoma
Published by:
http://www.rupress.org/
_version_ 1836398787353903104
autor Tissino, E., Benedetti, D., Herman, S. E. M., ten Hacken, E., Ahn, I. E., Chaffee, K. G., Rossi, F. M., Dal Bo, M., Bulian, P., Bomben, R., Bayer, E., Härzschel, A., Gutjahr, J. C., Postorino, M., Santinelli, E., Ayed, A., Zaja, F., Chiarenza, A., Pozzato, G., Chigaev, A., Sklar, L. A., Burger, J. A., Ferrajoli, A., Shanafelt, T. D., Wiestner, A., Del Poeta, G., Hartmann, T. N., Gattei, V., Zucchetto, A.
beschreibung 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.
citation_standardnr 6161231
datenlieferant ipn_articles
feed_id 96
feed_publisher Rockefeller University Press
feed_publisher_url http://www.rupress.org/
insertion_date 2018-02-10
journaleissn 1540-9538
journalissn 0022-1007
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher Rockefeller University Press
quelle Journal of Experimental Medicine
relation http://jem.rupress.org/cgi/content/short/215/2/681?rss=1
schlagwort Leukemia & Lymphoma
search_space articles
shingle_author_1 Tissino, E., Benedetti, D., Herman, S. E. M., ten Hacken, E., Ahn, I. E., Chaffee, K. G., Rossi, F. M., Dal Bo, M., Bulian, P., Bomben, R., Bayer, E., Härzschel, A., Gutjahr, J. C., Postorino, M., Santinelli, E., Ayed, A., Zaja, F., Chiarenza, A., Pozzato, G., Chigaev, A., Sklar, L. A., Burger, J. A., Ferrajoli, A., Shanafelt, T. D., Wiestner, A., Del Poeta, G., Hartmann, T. N., Gattei, V., Zucchetto, A.
shingle_author_2 Tissino, E., Benedetti, D., Herman, S. E. M., ten Hacken, E., Ahn, I. E., Chaffee, K. G., Rossi, F. M., Dal Bo, M., Bulian, P., Bomben, R., Bayer, E., Härzschel, A., Gutjahr, J. C., Postorino, M., Santinelli, E., Ayed, A., Zaja, F., Chiarenza, A., Pozzato, G., Chigaev, A., Sklar, L. A., Burger, J. A., Ferrajoli, A., Shanafelt, T. D., Wiestner, A., Del Poeta, G., Hartmann, T. N., Gattei, V., Zucchetto, A.
shingle_author_3 Tissino, E., Benedetti, D., Herman, S. E. M., ten Hacken, E., Ahn, I. E., Chaffee, K. G., Rossi, F. M., Dal Bo, M., Bulian, P., Bomben, R., Bayer, E., Härzschel, A., Gutjahr, J. C., Postorino, M., Santinelli, E., Ayed, A., Zaja, F., Chiarenza, A., Pozzato, G., Chigaev, A., Sklar, L. A., Burger, J. A., Ferrajoli, A., Shanafelt, T. D., Wiestner, A., Del Poeta, G., Hartmann, T. N., Gattei, V., Zucchetto, A.
shingle_author_4 Tissino, E., Benedetti, D., Herman, S. E. M., ten Hacken, E., Ahn, I. E., Chaffee, K. G., Rossi, F. M., Dal Bo, M., Bulian, P., Bomben, R., Bayer, E., Härzschel, A., Gutjahr, J. C., Postorino, M., Santinelli, E., Ayed, A., Zaja, F., Chiarenza, A., Pozzato, G., Chigaev, A., Sklar, L. A., Burger, J. A., Ferrajoli, A., Shanafelt, T. D., Wiestner, A., Del Poeta, G., Hartmann, T. N., Gattei, V., Zucchetto, A.
shingle_catch_all_1 Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia
Leukemia & Lymphoma
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.
Tissino, E., Benedetti, D., Herman, S. E. M., ten Hacken, E., Ahn, I. E., Chaffee, K. G., Rossi, F. M., Dal Bo, M., Bulian, P., Bomben, R., Bayer, E., Härzschel, A., Gutjahr, J. C., Postorino, M., Santinelli, E., Ayed, A., Zaja, F., Chiarenza, A., Pozzato, G., Chigaev, A., Sklar, L. A., Burger, J. A., Ferrajoli, A., Shanafelt, T. D., Wiestner, A., Del Poeta, G., Hartmann, T. N., Gattei, V., Zucchetto, A.
Rockefeller University Press
0022-1007
00221007
1540-9538
15409538
shingle_catch_all_2 Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia
Leukemia & Lymphoma
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.
Tissino, E., Benedetti, D., Herman, S. E. M., ten Hacken, E., Ahn, I. E., Chaffee, K. G., Rossi, F. M., Dal Bo, M., Bulian, P., Bomben, R., Bayer, E., Härzschel, A., Gutjahr, J. C., Postorino, M., Santinelli, E., Ayed, A., Zaja, F., Chiarenza, A., Pozzato, G., Chigaev, A., Sklar, L. A., Burger, J. A., Ferrajoli, A., Shanafelt, T. D., Wiestner, A., Del Poeta, G., Hartmann, T. N., Gattei, V., Zucchetto, A.
Rockefeller University Press
0022-1007
00221007
1540-9538
15409538
shingle_catch_all_3 Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia
Leukemia & Lymphoma
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.
Tissino, E., Benedetti, D., Herman, S. E. M., ten Hacken, E., Ahn, I. E., Chaffee, K. G., Rossi, F. M., Dal Bo, M., Bulian, P., Bomben, R., Bayer, E., Härzschel, A., Gutjahr, J. C., Postorino, M., Santinelli, E., Ayed, A., Zaja, F., Chiarenza, A., Pozzato, G., Chigaev, A., Sklar, L. A., Burger, J. A., Ferrajoli, A., Shanafelt, T. D., Wiestner, A., Del Poeta, G., Hartmann, T. N., Gattei, V., Zucchetto, A.
Rockefeller University Press
0022-1007
00221007
1540-9538
15409538
shingle_catch_all_4 Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia
Leukemia & Lymphoma
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.
Tissino, E., Benedetti, D., Herman, S. E. M., ten Hacken, E., Ahn, I. E., Chaffee, K. G., Rossi, F. M., Dal Bo, M., Bulian, P., Bomben, R., Bayer, E., Härzschel, A., Gutjahr, J. C., Postorino, M., Santinelli, E., Ayed, A., Zaja, F., Chiarenza, A., Pozzato, G., Chigaev, A., Sklar, L. A., Burger, J. A., Ferrajoli, A., Shanafelt, T. D., Wiestner, A., Del Poeta, G., Hartmann, T. N., Gattei, V., Zucchetto, A.
Rockefeller University Press
0022-1007
00221007
1540-9538
15409538
shingle_title_1 Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia
shingle_title_2 Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia
shingle_title_3 Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia
shingle_title_4 Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia
timestamp 2025-06-30T23:32:38.167Z
titel Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia
titel_suche Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia
topic WW-YZ
uid ipn_articles_6161231