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

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.

• Authors: Maike Buchner, Constance Baer, Gabriele Prinz, Christine Dierks, Meike Burger, Thorsten Zenz, Stephan Stilgenbauer, Hassan Jumaa, Hendrik Veelken, Katja Zirlik
• Journal: Blood (Blood) Vol. 115 Issue 22 Pg. 4497-506 (Jun 03 2010) ISSN: 1528-0020 [Electronic] United States
• PMID: 20335218 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• CXCL12 protein, human
• Chemokine CXCL12
• Chemokines
• Fibronectins
• Integrins
• Intracellular Signaling Peptides and Proteins
• Mcl1 protein, mouse
• Myeloid Cell Leukemia Sequence 1 Protein
• N4-(2,2-dimethyl-3-oxo-4H-pyrid(1,4)oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine
• Oxazines
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-bcl-2
• Pyridines
• RNA, Small Interfering
• Receptors, Antigen, B-Cell
• Vascular Cell Adhesion Molecule-1
• Integrin alpha4
• Protein-Tyrosine Kinases
• SYK protein, human
• Syk Kinase
• Syk protein, mouse
• Proto-Oncogene Proteins c-akt

Topics

• Actins (metabolism)
• Aged
• Animals
• Apoptosis (drug effects)
• Chemokine CXCL12 (metabolism)
• Chemokines (metabolism)
• Chemotaxis
• Coculture Techniques
• Female
• Fibronectins (metabolism)
• Humans
• Integrin alpha4 (metabolism)
• Integrins (metabolism)
• Intracellular Signaling Peptides and Proteins (antagonists & inhibitors, genetics, metabolism)
• Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy, metabolism, pathology)
• Male
• Mice
• Middle Aged
• Myeloid Cell Leukemia Sequence 1 Protein
• Oxazines (pharmacology)
• Prognosis
• Protein Kinase Inhibitors (pharmacology)
• Protein-Tyrosine Kinases (antagonists & inhibitors, genetics, metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Pyridines (pharmacology)
• RNA, Small Interfering (genetics)
• Receptors, Antigen, B-Cell (metabolism)
• Signal Transduction (drug effects)
• Stromal Cells (drug effects, metabolism)
• Syk Kinase
• Tumor Cells, Cultured
• Vascular Cell Adhesion Molecule-1 (metabolism)