Phosphatase inhibition augments anti-CD22-mediated signaling and cytotoxicity in non-hodgkin's lymphoma cells.
CD22 is a cell-surface molecule found on most B-cell lymphomas (NHL). HB22.7 is an anti-CD22 antibody that blocks CD22 ligand binding, initiates signaling, and kills NHL cells. The SHP-1 tyrosine phosphatase is disproportionately associated with the cytoplasmic domain of CD22. Sodium orthovanadate (NaV) and dephostatin (DP) are phosphatase inhibitors. The interaction of SHP-1 with CD22 presents an opportunity to manipulate CD22-mediated signaling effects. NaV caused dose dependent killing of NHL cells in vitro; when HB22.7 was given with NaV, antibody-mediated cell death increased. NaV caused a substantial increase in CD22-mediated SAPK and ERK-1/2 activation when CD22 was crosslinked by HB22.7; NaV did not significantly affect IgM-mediated signals. Studies using Raji NHL cells stably transfected with a SHP-1 dominant negative (DN) confirmed that these observations were due to SHP-1 inhibition. The relatively specific association of SHP-1 with CD22 suggests that CD22-specific signaling may be altered by phosphatase inhibition in ways that could prove useful for anti-CD22-based immunotherapy.
O'Donnell
Robert T
RT
Division of Hematology and Oncology, Department of Internal Medicine, University of California, Davis, Cancer Center, Veteran's Administration Northern California Healthcare System, United States.
Pearson
David
D
McKnight
Hayes C
HC
Ma
Ya Peng
YP
Tuscano
Joseph M
JM
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D005799:Genes, Dominant; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology*; D015151:Immunoblotting; D007075:Immunoglobulin M / Q000276:immunology / Q000378:metabolism; D008228:Lymphoma, Non-Hodgkin / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D014638:Vanadates / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D006873:Hydroquinones; D007075:Immunoglobulin M; C084037:dephostatin; D014638:Vanadates; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6