SYK inhibition and response prediction in diffuse large B-cell lymphoma

Abstract

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. A detailed analysis of the BCR signaling pathways revealed that the consequence of SYK inhibition on PLC␥2 and AKT, as opposed to ERK1/2, was responsible for cell-cycle arrest. Genetic knock-down of these key molecules decelerated the proliferation of lymphoma cells. In addition, BCR signaling can be blocked by PRT060318 in primary lymphoma cells. Together, these findings provide insights into cellular pathways required for lymphoma cell growth and support the rationale for considering SYK inhibition as a potentially useful therapy for DLBCL. The results further suggest the possibility of using PLC␥2 and AKT as biomarkers to predict therapeutic response in prospective clinical trials of specific SYK inhibitors. (Blood. 2011;118(24):6342-6352)

Role of the Immunoreceptor Tyrosine-Based Activation Motif of Latent Membrane Protein 2A (LMP2A) in Epstein-Barr Virus LMP2A-Induced Cell Transformation

“…Moreover, effects of the inhibitor's treatment on cell growth and cell toxicity were assessed with a cellcounting kit and trypan blue dye exclusion assay. In agreement with previous reports (34,38,39), genistein or piceatannol inhibited the growth of parental and LMP2A-expressing HSC-39, MCF-7, and 293 cells; also, genistein had more cytotoxic effects in those cells (data not shown). These results suggest that LMP2A-induced anchorage-independent cell growth is associated with general cell growth.…”

β2 integrin–derived signals induce cell survival and proliferation of AML blasts by activating a Syk/STAT signaling axis

“…For example, it has been shown that Syk acts as an oncoprotein in diffuse large B-cell lymphomas. 6,8 In contrast, loss of Syk function contributes to the onset of pro-/pre-Bcell leukemias by causing a differentiation block in the B-cell lineage. 9 Upon receptor stimulation, a phosphorylated immunoreceptor tyrosine-based activation motif (ITAM)/Syk-(SH2) 2 interaction induces an allosteric activation of Syk by changing the conformation of Syk from a closed, inactive structure to an open, active form.…”

Coming full circle: 70 years of chronic lymphocytic leukemia cell redistribution, from glucocorticoids to inhibitors of B-cell receptor signaling

“…One patient with CLL actually discontinued therapy because of lymphocytosis before the redistribution phenomenon was recognized. 20 More specific SYK inhibitors are active in preclinical models of CLL 83 and diffuse large B-cell lymphoma, 84 and we expected that SYK inhibitors will reappear on the clinical stage in selected B-cell malignancies in the near future. …”