Spleen Tyrosine Kinase Is Involved in the CD38 Signal Transduction Pathway in Chronic Lymphocytic Leukemia

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.

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Complementation by the protein tyrosine kinase JAK2 of a mutant cell line defective in the interferon-& gamma; signal transduction pathway

Nature ◽

10.1038/366166a0 ◽

1993 ◽

Vol 366 (6451) ◽

pp. 166-170 ◽

Cited By ~ 360

Author(s):

Diane Watling ◽

Dmitry Guschin ◽

Mathias Müller ◽

Olli Silvennoinen ◽

Bruce A. Witthuhn ◽

...

Keyword(s):

Signal Transduction ◽

Tyrosine Kinase ◽

Cell Line ◽

Interferon Gamma ◽

Protein Tyrosine Kinase ◽

Mutant Cell ◽

Signal Transduction Pathway ◽

Transduction Pathway ◽

Protein Tyrosine ◽

Mutant Cell Line

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Role of spleen tyrosine kinase in the pathogenesis of chronic lymphocytic leukemia

Leukemia & Lymphoma ◽

10.3109/10428194.2014.891026 ◽

2014 ◽

Vol 55 (12) ◽

pp. 2699-2705 ◽

Cited By ~ 7

Author(s):

Gege Feng ◽

Xin Wang

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Tyrosine Kinase ◽

Lymphocytic Leukemia ◽

Spleen Tyrosine Kinase

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Spleen tyrosine kinase inhibition prevents chemokine- and integrin-mediated stromal protective effects in chronic lymphocytic leukemia

Blood ◽

10.1182/blood-2009-07-233692 ◽

2010 ◽

Vol 115 (22) ◽

pp. 4497-4506 ◽

Cited By ~ 126

Author(s):

Maike Buchner ◽

Constance Baer ◽

Gabriele Prinz ◽

Christine Dierks ◽

Meike Burger ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Tyrosine Kinase ◽

Cell Receptor ◽

Lymphocytic Leukemia ◽

Cytotoxic Agents ◽

Protective Effects ◽

Spleen Tyrosine Kinase ◽

Growth And Survival ◽

Akt Phosphorylation ◽

Bcr Signaling

Abstract The microenvironment provides essential growth and survival signals to chronic lymphocytic leukemia (CLL) cells and contributes to their resistance to cytotoxic agents. Pharmacologic inhibition of spleen tyrosine kinase (SYK), a key mediator of B-cell receptor (BCR) signaling, induces apoptosis in primary CLL cells and prevents stroma contact-mediated cell survival. This report demonstrates a role of SYK in molecularly defined pathways that mediate the CLL-microenvironmental crosstalk independent from the BCR. Chemokine and integrin stimulation induced SYK phosphorylation, SYK-dependent Akt phosphorylation, and F-actin formation in primary CLL cells. Inhibition of SYK by 2 pharmacologic inhibitors and siRNA-knockdown abrogated downstream SYK signaling and morphologic changes induced by these stimuli. CLL cell migration toward CXCL12, the major homing attractor, and CLL cell adhesion to VCAM-1, a major integrin ligand expressed on stromal cells, were markedly reduced by SYK inhibition. In combination with fludarabine, the SYK inhibitor R406 abrogated stroma-mediated drug resistance by preventing up-regulation of the antiapoptotic factor Mcl-1 in CLL cells. SYK blockade in CLL is a promising therapeutic principle not only for its inhibition of the BCR signaling pathway, but also by inhibiting protective stroma signals in a manner entirely independent of BCR signaling.

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Gain-of-Function Mutations in the Caenorhabditis elegans lin-1 ETS Gene Identify a C-Terminal Regulatory Domain Phosphorylated by ERK MAP Kinase

Genetics ◽

10.1093/genetics/149.4.1809 ◽

1998 ◽

Vol 149 (4) ◽

pp. 1809-1822 ◽

Cited By ~ 5

Author(s):

Dave Jacobs ◽

Greg J Beitel ◽

Scott G Clark ◽

H Robert Horvitz ◽

Kerry Kornfeld

Keyword(s):

Signal Transduction ◽

Caenorhabditis Elegans ◽

Tyrosine Kinase ◽

Map Kinase ◽

Cell Fate ◽

Receptor Tyrosine Kinase ◽

Signal Transduction Pathway ◽

Negative Regulation ◽

Transduction Pathway ◽

C Terminus

Abstract Genetic analysis of lin-1 loss-of-function mutations suggests that lin-1 controls multiple cell-fate decisions during Caenorhabditis elegans development and is negatively regulated by a conserved receptor tyrosine kinase-Ras-ERK mitogen-activated protein (MAP) kinase signal transduction pathway. LIN-1 protein contains an ETS domain and presumably regulates transcription. We identified and characterized six gain-of-function mutations that define a new class of lin-1 allele. These lin-1 alleles appeared to be constitutively active and unresponsive to negative regulation. Each allele has a single-base change that affects the predicted C terminus of LIN-1, suggesting this region is required for negative regulation. The C terminus of LIN-1 was a high-affinity substrate for Erk2 in vitro, suggesting that LIN-1 is directly regulated by ERK MAP kinase. Because mpk-1 ERK MAP kinase controls at least one cell-fate decision that does not require lin-1, our results suggest that MPK-1 contributes to the specificity of this receptor tyrosine kinase-Ras-MAP kinase signal transduction pathway by phosphorylating different proteins in different developmental contexts. These lin-1 mutations all affect a four-amino-acid motif, FQFP, that is conserved in vertebrate and Drosophila ETS proteins that are also phosphorylated by ERK MAP kinase. This sequence may be a substrate recognition motif for the ERK subfamily of MAP kinases.

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