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Egr 1, a zinc finger transcription issue, shown to be critical for B lymphoma growth was also down regulated upon SFK inhibition. The data help an active role for Lyn kinase in mediating constitutive BCR signaling for lymphoma survival and development. The SFK induced growth inhibition can be partially conquer by treating the cells with PMA or unmethylated CpG ODN.

Given that PMA immediately BYL719 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 basic, the human B lymphoma cell lines essential higher doses of SFK inhibitors than murine B lymphoma cells to induce development inhibition. There was extremely minor apoptosis in the SFK inhibitor treated human B lymphomas. We showed that this could be connected to enhanced expression of anti apoptotic proteins Bcl 2 and Bcl xL by the human B lymphomas compared to the murine lymphomas.

Additionally, constitutive expression of Bcl xL created the WEHI 231 cell line less susceptible to SFK induced apoptosis. Our data recommend that the constitutive BCR signaling in B lymphoma cells is most likely due to constitutive activation of Lyn, the upstream enzyme required for tyrosine antigen peptide phosphorylation of Igand Ig. Our studies are in standard agreement with a recent report by Yang et al. about the effects of dasatinib on lymphoma development in vitro. They compared dasatinib to Imatinib to support the idea that SFK but not other tyrosine kinases are essential for lymphoma growth. Even so, proteomic approaches have demonstrated that dasatinib can affect other PTKs like BTK, Csk, as properly as other Ser/Thr kinases like p38 MAPK. As a result, our study utilized siRNA to especially knock down Lyn and thus demonstrated Lyn is needed for lymphoma development.

Additionally, we were in a position to demonstrate dasatinib efficacy in an in vivo lymphoma model. The evident question is: Why is Lyn kinase constitutively energetic in B lymphoma cells One particular chance is that Lyn is mutated in B lymphoma cells, which may be unlikely, because Lyn is active in a number of murine and human lymphoma cells. Yet another possibility is that Lyn is constitutively active PARP due to the association of Lyn with lipid rafts that dont consist of the damaging regulator Csk in B lymphoma cells. In normal 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, fast manufacturing of reactive oxygen species, in distinct H2O2.

The ROS in turn led to a speedy and transient inhibition of protein tyrosine phosphatase activity linked with the BCR due to the oxidation of the important cysteine in the energetic internet site of PTP and a transient boost in Lyn kinase activity.