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| Content Provider | PubMed Central |
|---|---|
| Author | Herman, Sarah E. M. Gordon, Amber L. Hertlein, Erin Ramanunni, Asha Zhang, Xiaoli Jaglowski, Samantha Flynn, Joseph Jones, Jeffrey Blum, Kristie A. Buggy, Joseph J. Hamdy, Ahmed Johnson, Amy J. Byrd, John C. |
| Copyright Year | 2011 |
| Abstract | B-cell receptor (BCR) signaling is aberrantly activated in chronic lymphocytic leukemia (CLL). Bruton tyrosine kinase (BTK) is essential to BCR signaling and in knockout mouse models its mutation has a relatively B cell–specific phenotype. Herein, we demonstrate that BTK protein and mRNA are significantly over expressed in CLL compared with normal B cells. Although BTK is not always constitutively active in CLL cells, BCR or CD40 signaling is accompanied by effective activation of this pathway. Using the irreversible BTK inhibitor PCI-32765, we demonstrate modest apoptosis in CLL cells that is greater than that observed in normal B cells. No influence of PCI-32765 on T-cell survival is observed. Treatment of CD40 or BCR activated CLL cells with PCI-32765 results in inhibition of BTK tyrosine phosphorylation and also effectively abrogates downstream survival pathways activated by this kinase including ERK1/2, PI3K, and NF-κB. In addition, PCI-32765 inhibits activation-induced proliferation of CLL cells in vitro, and effectively blocks survival signals provided externally to CLL cells from the microenvironment including soluble factors (CD40L, BAFF, IL-6, IL-4, and TNF-α), fibronectin engagement, and stromal cell contact. Based on these collective data, future efforts targeting BTK with the irreversible inhibitor PCI-32765 in clinical trials of CLL patients is warranted. |
| Related Links | http://dx.doi.org/10.1182/blood-2011-01-328484 |
| Ending Page | 6296 |
| Page Count | 10 |
| Starting Page | 6287 |
| File Format | |
| ISSN | 00064971 |
| e-ISSN | 15280020 |
| Journal | Blood |
| Issue Number | 23 |
| Volume Number | 117 |
| Language | English |
| Publisher | American Society of Hematology |
| Publisher Date | 2011-06-09 |
| Access Restriction | Open |
| Rights Holder | American Society of Hematology |
| Subject Keyword | Immunology Cell Biology Biochemistry Hematology Research in Higher Education |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Hematology Biochemistry Immunology |
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