The Role Of Heat Shock Factor 1 In Germinal Center B Cells And Lymphoma
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Diffuse large B cell lymphomas (DLBCLs) are a heterogeneous group of molecularly complex malignancies. The majority of DLBCL tumors arise from cells that are arrested in or have passed through the germinal center (GC). During the GC response, B cells undergo massive clonal expansion and somatic hypermutation of their immunoglobulin loci to produce high-affinity antibodies. Therefore GC B cells need to tolerate replicative and genotoxic stress without inducing cell cycle arrest, suggestive of a specialized stress response. Consistent with this hypothesis, we have discovered that a dominant regulator of the conserved stress response, heat shock factor 1 (HSF1), is important for the GC response. HSF1 regulates the stress-dependent induction of BCL6, an essential factor for GC formation that represses genes involved in DNA damage sensing and checkpoint activation. Hsf1-/- mice have smaller GCs and defects in the production of high-affinity antibodies. Because coordinate expression of genes is required for the GC response and post-GC differentiation, deregulation of certain genes, including BCL6, can lead to lymphomagenesis. Therefore the same pathways sustaining the GC response may be involved in maintaining DLBCL survival. We find that HSF1 controls a transcriptional program during the GC reaction that is necessary to tolerate stress associated with rapid replication and genomic instability. HSF1 is required to maintain the malignant phenotype in DLBCL due the regulation of genes involved in protein homeostasis and cell cycle control. We demonstrate that the stress axis of HSF1 and BCL6 is an evolutionarily conserved feature of vertebrates and BCL6 acts as a stress response gene. BCL6 mediates stress tolerance through a lateral groove on its BTB domain that forms docking sites for NCOR, SMRT, and BCOR corepressors. Genetic or pharmacologic disruption of this motif abrogated the stress tolerance function of BCL6. Notably, a survey of human tumor cells revealed that HSF1-dependent expression of BCL6 enables them to tolerate exposure to cytotoxic agents. Taken together, the evolutionarily conserved role of BCL6 and its BTB domain in mediating tolerance to stress in vertebrates provides the basis for using BCL6 BTB domain inhibitors as a broadly relevant therapeutic approach for cancer.
BCL6; DLBCL; germinal center; HSF1; lymphoma; stress response
Doctor of Philosophy
Attribution-NonCommercial-NoDerivatives 4.0 International
dissertation or thesis
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