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

Considering that PMA immediately Paclitaxel 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 caused 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 general, the human B lymphoma cell lines required larger doses of SFK inhibitors than murine B lymphoma cells to induce growth inhibition. There was really small apoptosis in the SFK inhibitor treated human B lymphomas. We showed that this could be related to elevated expression of anti apoptotic proteins Bcl 2 and Bcl xL by the human B lymphomas compared to the murine lymphomas.

Moreover, constitutive expression of Bcl xL made the WEHI 231 cell line much less vulnerable to SFK induced apoptosis. Our data recommend that the constitutive BCR signaling in B lymphoma cells is likely due to constitutive activation of Lyn, the upstream enzyme essential for tyrosine fluorescent peptides phosphorylation of Igand Ig. Our scientific 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 notion that SFK but not other tyrosine kinases are important for lymphoma development. Nevertheless, proteomic approaches have demonstrated that dasatinib can affect other PTKs like BTK, Csk, as well as other Ser/Thr kinases like p38 MAPK. Consequently, our study utilised siRNA to particularly knock down Lyn and hence demonstrated Lyn is essential for lymphoma development.

Furthermore, we were in a position 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 probability is that Lyn is mutated in B lymphoma cells, which may possibly be unlikely, because Lyn is energetic in a number of murine and human lymphoma cells. One more probability is that Lyn is constitutively active NSCLC due to the association of Lyn with lipid rafts that dont consist of the unfavorable regulator Csk in B lymphoma cells. In typical 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 production of reactive oxygen species, in specific H2O2.

The ROS in turn led to a quick and transient inhibition of protein tyrosine phosphatase activity associated with the BCR due to the oxidation of the critical cysteine in the active web site of PTP and a transient boost in Lyn kinase activity. In addition, modern outbreaks of MPX in BYL719 the United States and in the Democratic Republic of Congo have raised the prospect that emergent poxviruses may possibly also pose a significant threat.