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

Abstract

The survival and proliferation of CLL cells depends on microenvironmental contacts in lymphoid organs. CD38 is a cell surface receptor that plays an important role in survival and proliferation signaling in CLL. In this study we demonstrate SYK's direct involvement in the CD38 signaling pathway in primary CLL samples. CD38 stimulation of CLL cells revealed SYK activation. SYK downstream target AKT was subsequently induced and MCL-1 expression was increased. Concomitant inhibition of SYK by the SYK inhibitor R406 resulted in reduced activation of AKT and prevented upregulation of MCL-1. Moreover, short-term CD38 stimulation enhanced BCR-signaling, as indicated by increased ERK phosphorylation. CXCL12-dependent migration was increased after CD38 stimulation. Treating CLL cells with R406 inhibited CD38-mediated migration. In addition, we observed marked downregulation of CD38 expression for CLL cells treated with R406 compared to vehicle control. Finally, we observed a clear correlation between CD38 expression on CLL cells and SYK-inhibitor efficacy. In conclusion, our study provides deeper mechanistic insight into the effect of SYK inhibition in CLL.

• Authors: Marco Benkisser-Petersen, Maike Buchner, Arlette Dörffel, Marcus Dühren-von-Minden, Rainer Claus, Kathrin Kläsener, Kerstin Leberecht, Meike Burger, Christine Dierks, Hassan Jumaa, Fabio Malavasi, Michael Reth, Hendrik Veelken, Justus Duyster, Katja Zirlik
• Journal: PloS one (PLoS One) Vol. 11 Issue 12 Pg. e0169159 ( 2016) ISSN: 1932-6203 [Electronic] United States
• PMID: 28036404 (Publication Type: Journal Article)

Chemical References

• CXCL12 protein, human
• Chemokine CXCL12
• MCL1 protein, human
• Membrane Glycoproteins
• 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
• Pyridines
• SYK protein, human
• Syk Kinase
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases
• CD38 protein, human
• ADP-ribosyl Cyclase 1

Topics

• ADP-ribosyl Cyclase 1 (biosynthesis, metabolism, pharmacology)
• Adult
• Aged
• Aged, 80 and over
• Apoptosis (drug effects)
• Cell Movement (drug effects)
• Cell Survival
• Chemokine CXCL12 (metabolism)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• Humans
• Leukemia, Lymphocytic, Chronic, B-Cell (pathology)
• Male
• Membrane Glycoproteins (biosynthesis, metabolism, pharmacology)
• Middle Aged
• Myeloid Cell Leukemia Sequence 1 Protein (biosynthesis)
• Oxazines (pharmacology)
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyridines (pharmacology)
• Syk Kinase (antagonists & inhibitors, metabolism)
• Tumor Cells, Cultured