scholarly journals B-cell antigen receptor signaling enhances chronic lymphocytic leukemia cell migration and survival: specific targeting with a novel spleen tyrosine kinase inhibitor, R406

Blood ◽  
2009 ◽  
Vol 114 (5) ◽  
pp. 1029-1037 ◽  
Author(s):  
Maite P. Quiroga ◽  
Kumudha Balakrishnan ◽  
Antonina V. Kurtova ◽  
Mariela Sivina ◽  
Michael J. Keating ◽  
...  
Keyword(s):  
Cell Migration ◽  
Chronic Lymphocytic Leukemia ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Antigen Receptor ◽  
Lymphocytic Leukemia ◽  
B Cell Antigen Receptor ◽  
Spleen Tyrosine Kinase ◽  
Cell Antigen Receptor ◽  
Cell Antigen

Antigenic stimulation through the B-cell antigen receptor (BCR) is considered to promote the expansion of chronic lymphocytic leukemia (CLL) B cells. The spleen tyrosine kinase (Syk), a key component of BCR signaling, can be blocked by R406, a small-molecule Syk inhibitor, that displayed activity in CLL patients in a first clinical trial. In this study, we investigated the effects of BCR stimulation and R406 on CLL cell survival and migration. The prosurvival effects promoted by anti-IgM stimulation and nurselike cells were abrogated by R406. BCR triggering up-regulated adhesion molecules, and increased CLL cell migration toward the chemokines CXCL12 and CXCL13. BCR activation also enhanced CLL cell migration beneath marrow stromal cells. These responses were blocked by R406, which furthermore abrogated BCR-dependent secretion of T-cell chemokines (CCL3 and CCL4) by CLL cells. Finally, R406 inhibited constitutive and BCR-induced activation of Syk, extracellular signal-regulated kinases, and AKT, and blocked BCR-induced calcium mobilization. These findings suggest that BCR activation favors CLL cell homing, retention, and survival in tissue microenvironments. R406 effectively blocks these BCR-dependent responses in CLL cells, providing an explanation for the activity of R406 in patients with CLL.

scholarly journals The B cell antigen receptor in atypical chronic lymphocytic leukemia with t(14;19)(q32;q13) demonstrates remarkable stereotypy

2010 ◽  
Vol 128 (11) ◽  
pp. 2759-2764 ◽  
Author(s):  
Carmen D. Schweighofer ◽  
Yang O. Huh ◽  
Rajyalakshmi Luthra ◽  
Rachel L. Sargent ◽  
Rhett P. Ketterling ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Antigen Receptor ◽  
Lymphocytic Leukemia ◽  
B Cell Antigen Receptor ◽  
Cell Antigen Receptor ◽  
Cell Antigen

Identification of the SH2 Domain Binding Protein of Bruton’s Tyrosine Kinase as BLNK—Functional Significance of Btk-SH2 Domain in B-Cell Antigen Receptor-Coupled Calcium Signaling

Blood ◽  
1999 ◽  
Vol 94 (7) ◽  
pp. 2357-2364 ◽  
Author(s):  
Shoji Hashimoto ◽  
Akihiro Iwamatsu ◽  
Masamichi Ishiai ◽  
Katsuya Okawa ◽  
Tomoki Yamadori ◽  
...  
Keyword(s):  
B Cells ◽  
Tyrosine Kinase ◽  
Calcium Signaling ◽  
B Cell ◽  
Functional Significance ◽  
Antigen Receptor ◽  
Sh2 Domain ◽  
B Cell Antigen Receptor ◽  
Cell Antigen Receptor ◽  
Cell Antigen

Bruton’s tyrosine kinase (Btk) is a critical component in the B-cell antigen receptor (BCR)-coupled signaling pathway. Its deficiency in B cells leads to loss or marked reduction in the BCR-induced calcium signaling. It is known that this BCR-induced calcium signaling depends on the activation of phospholipase Cγ (PLCγ), which is mediated by Btk and another tyrosine kinase Syk and that the SH2 and pleckstrin homology (PH) domains of Btk play important roles in this activation process. Although the importance of the PH domain of Btk has been explained by its role in the membrane targeting of Btk, the functional significance of the SH2 domain in the calcium signaling has remained merely a matter of speculation. In this report, we identify that one of the major Btk-SH2 domain-binding proteins in B cells is BLNK (B-cell linker protein) and present evidences that the interaction of BLNK and the SH2 domain of Btk contributes to the complete tyrosine phosphorylation of PLCγ.

Association of B cell antigen receptor with protein tyrosine kinase Lyn

Science ◽  
1991 ◽  
Vol 251 (4990) ◽  
pp. 192-194 ◽  
Author(s):  
Y Yamanashi ◽  
T Kakiuchi ◽  
J Mizuguchi ◽  
T Yamamoto ◽  
K Toyoshima
Keyword(s):  
Tyrosine Kinase ◽  
B Cell ◽  
Protein Tyrosine Kinase ◽  
Antigen Receptor ◽  
B Cell Antigen Receptor ◽  
Cell Antigen Receptor ◽  
Protein Tyrosine ◽  
Cell Antigen

scholarly journals Cbl-b Negatively Regulates B Cell Antigen Receptor Signaling in Mature B Cells through Ubiquitination of the Tyrosine Kinase Syk

2003 ◽  
Vol 197 (11) ◽  
pp. 1511-1524 ◽  
Author(s):  
Hae Won Sohn ◽  
Hua Gu ◽  
Susan K. Pierce
Keyword(s):  
B Cells ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Antigen Receptor ◽  
Cellular Systems ◽  
Cross Linking ◽  
B Cell Antigen Receptor ◽  
Cell Antigen Receptor ◽  
Cell Antigen ◽  
Bcr Signaling

Members of the Cbl family of molecular adaptors play key roles in regulating tyrosine kinase-dependent signaling in a variety of cellular systems. Here we provide evidence that in B cells Cbl-b functions as a negative regulator of B cell antigen receptor (BCR) signaling during the normal course of a response. In B cells from Cbl-b–deficient mice cross-linking the BCRs resulted in sustained phosphorylation of Igα, Syk, and phospholipase C (PLC)-γ2, leading to prolonged Ca2+ mobilization, and increases in extracellular signal–regulated kinase (ERK) and c-Jun NH2-terminal protein kinase (JNK) phosphorylation and surface expression of the activation marker, CD69. Image analysis following BCR cross-linking showed sustained polarization of the BCRs into large signaling-active caps associated with phosphorylated Syk in Cbl-b–deficient B cells in contrast to the BCRs in Cbl-b–expressing B cells that rapidly proceeded to form small, condensed, signaling inactive caps. Significantly, prolonged phosphorylation of Syk correlated with reduced ubiquitination of Syk indicating that Cbl-b negatively regulates BCR signaling by targeting Syk for ubiquitination.

Association with B-cell-antigen receptor with protein-tyrosine kinase p72syk and activation by engagement of membrane IgM

1993 ◽  
Vol 213 (1) ◽  
pp. 455-459 ◽  
Author(s):  
Takechiyo YAMADA ◽  
Takanobu TANIGUCHI ◽  
Cheng YANG ◽  
Satoshi YASUE ◽  
Hitoshi SAITO ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
B Cell ◽  
Protein Tyrosine Kinase ◽  
Antigen Receptor ◽  
B Cell Antigen Receptor ◽  
Cell Antigen Receptor ◽  
Protein Tyrosine ◽  
Cell Antigen
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