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Egr 1, a zinc finger transcription issue, shown to be essential for B lymphoma growth was also down regulated on SFK inhibition. The information support an energetic part for Lyn kinase in mediating constitutive BCR signaling for lymphoma survival and growth. The SFK induced growth inhibition can be partially conquer by treating the cells with PMA or unmethylated CpG ODN.

Considering that PMA immediately Factor Xa activates the BCR downstream kinase, Protein Kinase C, consequently ERK and Egr 1, this suggests that the active PKC ERK pathway can partially circumvent the blocking of BCR signaling triggered by SFK inhibition. CpG activates Toll like receptor 9 mediated signaling pathways. CpG can rescue immature B lymphoma cells from BCR mediated apoptosis by inducing a sustained activation of NF B, and subsequent expression of Bcl xL and c Myc and an up regulation of Egr 1. In standard, the human B lymphoma cell lines necessary increased doses of SFK inhibitors than murine B lymphoma cells to induce development inhibition. There was really little apoptosis in the SFK inhibitor taken care of human B lymphomas. We showed that this could be relevant to enhanced expression of anti apoptotic proteins Bcl 2 and Bcl xL by the human B lymphomas compared to the murine lymphomas.

Furthermore, constitutive expression of Bcl xL made the WEHI 231 cell line much less vulnerable to SFK induced apoptosis. Our data propose that the constitutive BCR signaling in B lymphoma cells is most likely due to constitutive activation of Lyn, the upstream enzyme necessary for tyrosine oligopeptide synthesis phosphorylation of Igand Ig. Our studies are in common agreement with a current report by Yang et al. about the effects of dasatinib on lymphoma development in vitro. They compared dasatinib to Imatinib to help the notion that SFK but not other tyrosine kinases are essential for lymphoma development. Even so, proteomic approaches have demonstrated that dasatinib can impact other PTKs like BTK, Csk, as effectively as other Ser/Thr kinases like p38 MAPK. As a result, our study used siRNA to specifically knock down Lyn and thus demonstrated Lyn is required for lymphoma growth.

Additionally, we have been ready to show dasatinib efficacy in an in vivo lymphoma model. The evident query is: Why is Lyn kinase constitutively active in B lymphoma cells One possibility is that Lyn is mutated in B lymphoma cells, which may be unlikely, given that Lyn is energetic in a amount of murine and human lymphoma cells. An additional possibility is that Lyn is constitutively active NSCLC due to the association of Lyn with lipid rafts that dont contain the negative regulator Csk in B lymphoma cells. In regular B cells, Lyn is only transiently activated in response to BCR engagement by antigen. Singh et al showed that BCR engagement led to a Ca2 dependent, speedy manufacturing of reactive oxygen species, in particular H2O2.

The ROS in turn led to a quick and transient inhibition of protein tyrosine phosphatase activity connected with the BCR due to the oxidation of the important cysteine in the energetic web site of PTP and a transient increase in Lyn kinase activity.