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The clinically active BTK inhibitor PCI-32765 targets B-cell receptor– and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia
Abstract
Small-molecule drugs that target the B-cell antigen receptor (BCR) signalosome show clinical efficacy in the treatment of B-cell non-Hodgkin lymphoma. These agents, including the Bruton tyrosine kinase (BTK) inhibitor PCI-32765, display an unexpected response in patients with chronic lymphocytic leukemia (CLL): a rapid and sustained reduction of lymphadenopathy accompanied by transient lymphocytosis, which is reversible upon temporary drug deprivation. We hypothesized that this clinical response reflects impaired integrin-mediated adhesion and/or migration. Here, we show that PCI-32765 strongly inhibits BCR-controlled signaling and integrin α4β1-mediated adhesion to fibronectin and VCAM-1 of lymphoma cell lines and primary CLL cells. Furthermore, PCI-32765 also inhibits CXCL12-, CXCL13-, and CCL19-induced signaling, adhesion, and migration of primary CLL cells. Our data indicate that inhibition of BTK by PCI-32765 overcomes BCR- and chemokine-controlled integrin-mediated retention and homing of malignant B cells in their growth- and survival-supporting lymph node and bone marrow microenvironment, which results in clinically evident CLL regression.
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Cited by
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Self-citationAdvani, R. H., Buggy, J. J., Sharman, J. P., Smith, S. M., Boyd, T. E., Grant, B., Kolibaba, K. S., Furman, R. R., Rodriguez, S., Chang, B. Y., et al. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.42.7906 · Cited by 1,128
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Metadata
- Authors
- de Rooij, M. F. M., Kuil, A., Geest, C. R., Eldering, E., Chang, B. Y., Buggy, J. J., Pals, S. T., & Spaargaren, M.
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2012-03-15
- Volume
- 119
- Issue
- 11
- Pages
- 2590-2594
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2065338378
- Cited by
- 554
- References
- 0
- FWCI
- 28.31
- Type
- journal article
- Language
- en
- Open access
- closed
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- CoChat. (2026). Citation check: The clinically active BTK inhibitor PCI-32765 targets B-cell receptor– and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. https://app.cochat.ai/papers/10.1182/blood-2011-11-390989
- The paper
- de Rooij, M. F. M., Kuil, A., Geest, C. R., Eldering, E., Chang, B. Y., Buggy, J. J., Pals, S. T., & Spaargaren, M. (2012). The clinically active BTK inhibitor PCI-32765 targets B-cell receptor– and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood. https://doi.org/10.1182/blood-2011-11-390989
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