Diffuse large B cell lymphomas (DLBCLs) are a heterogeneous group of malignancies, the complexity of which still remains to be fully resolved. 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 knockout mice have smaller GCs and defects in the production of high-affinity antibodies. Moreover we have found that HSF1 regulates the expression of BCL6, an essential factor for the GC response that represses genes involved in DNA damage sensing and checkpoint activation. 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 hypothesize that HSF1 controls a transcriptional program during the GC reaction that is necessary to tolerate stress associated with rapid replication and genomic instability. It is anticipated that HSF1, via the regulation of subset of genes, is required to maintain the malignant phenotype in DLBCL. To test this hypothesis, we will determine the HSF1 transcriptional program that is induced in the GC response and DLBCL via HSF1 ChIP-seq and gene expression analysis (mRNA-seq) in normal human tonsil-derived na?ve and GC B cells and in malignant human DLBCL cell lines and primary DLBCL patient samples. We will identify if HSF1 is crucial for DLBCL survival and explore the HSF1 target genes that are mediating malignancy. These proposed experiments will evaluate a role for HSF1 in B cell activation and DLBCL. These studies will not only elucidate a novel therapeutic target in lymphoma but will also provide valuable mechanistic insight into the transcriptional regulation of genes important for lymphoma development and survival.
The proposed research will significantly advance our understanding of how stress-mediated signaling pathways contribute to the development and survival of diffuse large B cell lymphoma (DLBCL). The identification of the gene networks involved in transformation will provide additional avenues to improve and specify therapies for the treatment of DLBCL, the most common form of aggressive lymphoid malignancies.
