Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia
| العنوان: | Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia |
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| المؤلفون: | Tanja Nicole Hartmann, Ayed O. Ayed, Alexandre Chigaev, Valter Gattei, Gabriele Pozzato, Antonella Zucchetto, Enrico Santinelli, Jan A. Burger, Julia Christine Gutjahr, Massimiliano Postorino, Elisabeth Bayer, Erika Tissino, Riccardo Bomben, Giovanni Del Poeta, Michele Dal Bo, Adrian Wiestner, Elisa Ten Hacken, Dania Benedetti, Pietro Bulian, Inhye E. Ahn, Larry A. Sklar, Andrea Härzschel, Alessandra Ferrajoli, Francesca Rossi, Kari G. Chaffee, Annalisa Chiarenza, Francesco Zaja, Tait D. Shanafelt, Sarah E. M. Herman |
| المساهمون: | Tissino, Erika, Benedetti, Dania, Herman, Sarah E. M., ten Hacken, Elisa, Ahn, Inhye E., Chaffee, Kari G., Rossi, Francesca Maria, Bo, Michele Dal, 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 |
| المصدر: | The Journal of Experimental Medicine |
| بيانات النشر: | Rockefeller University Press, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Lymphocytosis, Chronic lymphocytic leukemia, CLL, BTK, CD49, Kaplan-Meier Estimate, Integrin alpha4beta1, CD49d, Phosphatidylinositol 3-Kinases, chemistry.chemical_compound, 0302 clinical medicine, Piperidines, immune system diseases, hemic and lymphatic diseases, Receptors, Agammaglobulinaemia Tyrosine Kinase, Immunology and Allergy, Chronic, Research Articles, Phosphoinositide-3 Kinase Inhibitors, Leukemia, biology, breakpoint cluster region, Lymphocytic, Progression-Free Survival, Antigen, 030220 oncology & carcinogenesis, Ibrutinib, medicine.symptom, Immunology, B-cell receptor, Cell Adhesion, Humans, Immunoglobulin M, Leukemia, Lymphocytic, Chronic, B-Cell, Lymph Nodes, Multivariate Analysis, Proportional Hazards Models, Protein Kinase Inhibitors, Pyrazoles, Pyrimidines, Receptors, Antigen, B-Cell, Article, 03 medical and health sciences, medicine, Bruton's tyrosine kinase, business.industry, Adenine, B-Cell, Settore MED/15, medicine.disease, chemistry, biology.protein, Cancer research, business, 030215 immunology |
| الوصف: | Tissino et al. demonstrate that in chronic lymphocytic leukemia, the VLA-4 (CD49d/CD29) integrin remains activable by B cell receptor stimulation also upon in vitro and in vivo ibrutinib exposure. Clinically, ibrutinib-treated CD49d-positive CLL patients experience reduced recirculation lymphocytosis and nodal response and inferior outcomes. 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. |
| وصف الملف: | STAMPA |
| تدمد: | 1540-9538 0022-1007 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1ce20e6cf679172aaf2fdf97325f1a46 https://doi.org/10.1084/jem.20171288 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....1ce20e6cf679172aaf2fdf97325f1a46 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15409538 00221007 |
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