The BCL6 oncogene plays a crucial role in sustaining diffuse large B-cell lymphomas (DLBCL) through transcriptional repression of key checkpoint genes. BCL6-targeted therapy kills lymphoma cells by releasing these checkpoints. However BCL6 also directly represses several DLBCL oncogenes such as BCL2 and BCL-XL that promote lymphoma survival. Herein we show that DLBCL cells that survive BCL6-targeted therapy induce a phenomenon of “oncogene-addiction switching” by reactivating BCL2-family dependent anti-apoptotic pathways. Thus, most DLBCL cells require concomitant inhibition of BCL6 and BCL2-family members for effective lymphoma killing. Moreover, in DLBCL cells initially resistant to BH3 mimetic drugs, BCL6 inhibition induces a newly developed reliance on anti-apoptotic BCL2-family members for survival that translates in acquired susceptibility to BH3 mimetic drugs ABT-737 and obatoclax. In germinal center B cell-like (GCB)-DLBCL cells, the proteasome inhibitor bortezomib and the NEDD inhibitor MLN4924 post-transcriptionally activated the BH3-only sensitizer NOXA thus counteracting the oncogenic switch to BCL2 induced by BCL6-targeting. Hence our study indicates that BCL6 inhibition induces an on-target feedback mechanism based on the activation of anti-apoptotic BH3 members. This oncogene-addition switching mechanism was harnessed to develop rational combinatorial therapies for GCB-DLBCL.

Database management systems (DBMS) have been widely used for storing and retrieving data. However, databases are often hard to use since their interface is quite rigid in cooperating with users. End user is required to issue SQL query to retrieve information from the database. Thus, a user cannot interact directly because of lack of knowledge about the SQL query form, thus is restricted to available application options. To provide the direct access of user on dataset, some unstructured query processor is required. The present work is an interface that will convert the unstructured text query to structured SQL query. It is an intelligent interface formation between the user and the dataset and defined in three main stages namely Descriptive Database Construction, Unstructured Query Filtration and Mapping Stage. The system provide the robustness in terms to handle the broader range of user queries and is be implemented in java environment on Enterprise Employee Database.

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