title: 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.affiliation: Department of Hematology, Oncology and Stem cell transplantation, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.|Faculty of Biology, University of Freiburg, Freiburg, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Benkisser-Petersen
authors.affiliation: Institute for Clinical Chemistry and Pathobiochemistry, Technische Universität München, München, Germany.
authors.forename: Maike
authors.initials: M
authors.lastname: Buchner
authors.affiliation: Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Arlette
authors.initials: A
authors.lastname: Dörffel
authors.affiliation: Department of Immunology, University Medical Center, Ulm, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Dühren-von-Minden
authors.affiliation: Department of Hematology, Oncology and Stem cell transplantation, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Claus
authors.affiliation: BIOSS Centre for Biological Signalling Studies, Department of Molecular Immunology, Biology III, University of Freiburg, Freiburg, Germany.|Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Kläsener
authors.affiliation: BIOSS Centre for Biological Signalling Studies, Department of Molecular Immunology, Biology III, University of Freiburg, Freiburg, Germany.|Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Leberecht
authors.affiliation: Department of Hematology, Oncology and Stem cell transplantation, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Meike
authors.initials: M
authors.lastname: Burger
authors.affiliation: Department of Hematology, Oncology and Stem cell transplantation, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Dierks
authors.affiliation: Department of Immunology, University Medical Center, Ulm, Germany.
authors.forename: Hassan
authors.initials: H
authors.lastname: Jumaa
authors.affiliation: Department of Medical Sciences, Laboratory of Immunogenetics and CeRMS, University of Torino, and Transplant Immunology, Torino, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Malavasi
authors.affiliation: BIOSS Centre for Biological Signalling Studies, Department of Molecular Immunology, Biology III, University of Freiburg, Freiburg, Germany.|Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Reth
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Veelken
authors.affiliation: Department of Hematology, Oncology and Stem cell transplantation, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Justus
authors.initials: J
authors.lastname: Duyster
authors.affiliation: Department of Hematology, Oncology and Stem cell transplantation, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Katja
authors.identifier: http://orcid.org/0000-0001-6588-3076
authors.initials: K
authors.lastname: Zirlik
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000096:biosynthesis / Q000378:metabolism* / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival; D054377:Chemokine CXCL12 / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000378:metabolism* / Q000494:pharmacology; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000096:biosynthesis*; D010078:Oxazines / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D000072377:Syk Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; C579095:MCL1 protein, human; D008562:Membrane Glycoproteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C510788:N4-(2,2-dimethyl-3-oxo-4H-pyrid(1,4)oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine; D010078:Oxazines; D011725:Pyridines; C000606896:SYK protein, human; D000072377:Syk Kinase; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1