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Transitional b cell syk pathway

Jiao Ma, Wei Xing, Greg Coffey, Karen Dresser, Kellie Lu, Ailin Guo, Gordana Raca, Anjali Pandey, Pamela Conley, Hongbo Yu, Y Lynn Wang
B-cell receptor (BCR) and JAK/STAT pathways play critical roles in diffuse large B-cell lymphoma (DLBCL). Herein, we investigated the anti-lymphoma activity of cerdulatinib, a novel compound that dually targets SYK and JAK/STAT pathways. On a tissue microarray of 62 primary DLBCL tumors, 58% expressed either phosphorylated SYK or STAT3 or both. SYK and STAT3 are also phosphorylated in a panel of eleven DLBCL cell lines although ABC and GCB subtypes exhibited different JAK/STAT and BCR signaling profiles. In both ABC and GCB cell lines, cerdulatinib induced apoptosis that was associated with caspase-3 and PARP cleavage...
December 22, 2015: Oncotarget
Susann Hüttl, Kathrin Kläsener, Michaela Schweizer, Janna Schneppenheim, Hans-Heinrich Oberg, Dieter Kabelitz, Michael Reth, Paul Saftig, Bernd Schröder
The invariant chain (CD74), a chaperone in MHC class II-mediated Ag presentation, is sequentially processed by different endosomal proteases. We reported recently that clearance of the final membrane-bound N-terminal fragment (NTF) of CD74 is mediated by the intramembrane protease signal peptide peptidase-like (SPPL)2a, a process critical for B cell development. In mice, SPPL2a deficiency provokes the accumulation of this NTF in endocytic vesicles, which leads to a B cell maturation arrest at the transitional 1 stage...
August 15, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
Paul M Barr, Chungwen Wei, James Roger, Julia Schaefer-Cutillo, Jennifer L Kelly, Alexander F Rosenberg, John Jung, Iñaki Sanz, Jonathan W Friedberg
Cell signaling initiated by the B cell receptor is critical to normal development of B lymphocytes, most notably at the transitional B cell stage. Inhibition of this signaling pathway with the syk inhibitor, fostamatinib, has produced significant efficacy in lymphoid malignancies and autoimmune conditions. Here, we demonstrate that short-term use of fostamatinib impairs B lymphocyte development at the transitional stage without affecting mature B cell populations. Additionally, IL-10 producing B cells remained relatively constant throughout the treatment period...
March 2012: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Shuhua Cheng, Greg Coffey, X Hannah Zhang, Rita Shaknovich, Zibo Song, Pin Lu, Anjali Pandey, Ari M Melnick, Uma Sinha, Y Lynn Wang
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, and the role of SYK in its pathogenesis is not completely understood. Using tissue microarray, we demonstrated for the first time that SYK protein is activated in 27 of 61 (44%) primary human DLBCL tissues. Among DLBCL cell lines, 7 were sensitive and 3 were resistant to a highly specific SYK inhibitor, PRT060318. In sensitive DLBCL cells, SYK inhibition blocked the G(1)-S transition and caused cell-cycle arrest. This effect was reproduced by genetic reduction of SYK using siRNA...
December 8, 2011: Blood
Haifeng Song, Juan Zhang, Y Jeffrey Chiang, Reuben P Siraganian, Richard J Hodes
Deficiency in the adaptor protein B cell linker protein (BLNK) results in a substantial but incomplete block in B cell development, suggesting that alternative pathways exist for B lineage differentiation. Another adaptor protein, c-Cbl, plays a negative regulatory role in several BCR-signaling pathways. We therefore investigated the role of c-Cbl during B cell development and addressed the possibility that redundancies in pathways for B cell differentiation could be further revealed by eliminating negative effects mediated by c-Cbl...
January 15, 2007: Journal of Immunology: Official Journal of the American Association of Immunologists
Rachael Siegel, Unkyu Kim, Alina Patke, Xin Yu, Xiaodi Ren, Alexander Tarakhovsky, Robert G Roeder
OCA-B was originally identified as a nuclear transcriptional coactivator that is essential for antigen-driven immune responses. The later identification of a membrane bound, myristoylated form of OCA-B suggested additional, unique functions in B cell signaling pathways. This study has shown that OCA-B also functions in the pre-B1-to-pre-B2 cell transition and, most surprisingly, that it directly interacts with SYK, a tyrosine kinase critical for pre-BCR and BCR signaling. This unprecedented type of interaction-a transcriptional coactivator with a signaling kinase-occurs in the cytoplasm and directly regulates SYK stability...
May 19, 2006: Cell
Sandra Lavens, Emmanuel A Faust, Fang Lu, Michele Jacob, Messele Leta, Paul M Lieberman, Ellen Puré
Epstein-Barr Virus (EBV) is a potentially oncogenic herpesvirus that infects >90% of the world's population. EBV exists predominantly as a latent infection in B lymphocytes, with periodic lytic-cycle reactivation essential for cellular and host transmission. Viral reactivation can be stimulated by ligand-induced activation of B-cell-receptor (BCR)-coupled signaling pathways. The critical first step in the transition from latency to the lytic cycle is the expression of the viral immediate-early gene BZLF1 through the transcription activation of its promoter, Zp...
August 2004: Journal of Virology
R Pappu, A M Cheng, B Li, Q Gong, C Chiu, N Griffin, M White, B P Sleckman, A C Chan
Linker proteins function as molecular scaffolds to localize enzymes with substrates. In B cells, B cell linker protein (BLNK) links the B cell receptor (BCR)-activated Syk kinase to the phosphoinositide and mitogen-activated kinase pathways. To examine the in vivo role of BLNK, mice deficient in BLNK were generated. B cell development in BLNK-/- mice was blocked at the transition from B220+CD43+ progenitor B to B220+CD43- precursor B cells. Only a small percentage of immunoglobulin M++ (IgM++), but not mature IgMloIgDhi, B cells were detected in the periphery...
December 3, 1999: Science
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