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

Benkisser-Petersen, M., Buchner, M., Dörffel, A., Dühren-von-Minden, M., Claus, R., Kläsener, K., et al. (2016). Spleen Tyrosine Kinase Is Involved in the CD38 Signal Transduction Pathway in Chronic Lymphocytic Leukemia. PLoS One, 11, e0169159. doi:10.1371/journal.pone.0169159.

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Benkisser-Petersen, Marco1, Author
Buchner, Maike1, Author
Dörffel, Arlette1, Author
Dühren-von-Minden, Marcus1, Author
Claus, Rainer1, Author
Kläsener, Kathrin2, Author
Leberecht, Kerstin2, Author
Burger, Meike1, Author
Dierks, Christine1, Author
Jumaa, Hassan1, Author
Malavasi, Fabio1, Author
Reth, Michael2, Author
Veelken, Hendrik1, Author
Duyster, Justus1, Author
Zirlik, Katja1, Author
Affiliations:
1External Organizations, ou_persistent22              
2Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, 79108 Freiburg, DE, ou_2243640              

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 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.

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Language(s): eng - English
 Dates: 2016-12-30
 Publication Status: Issued
 Pages: -
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 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1371/journal.pone.0169159
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Title: PLoS One
Source Genre: Journal
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Publ. Info: San Francisco, CA : Public Library of Science
Pages: - Volume / Issue: 11 Sequence Number: - Start / End Page: e0169159 Identifier: ISSN: 1932-6203
CoNE: https://pure.mpg.de/cone/journals/resource/1000000000277850