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Elucidating the Mechanisms by which Mutations in Histone Modifying Genes Contribute to Lymphomagenesis

Emilia Lim

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Canadian Institutes of Health Research (CIHR)
Lymphomas are aggressive cancers of the immune system. Non-Hodgkin Lymphomas (NHL), specifically Diffuse Large B-Cell Lymphoma (DLBCL), have a post-treatment survival rate of <50%. Histones are the proteins that provide DNA with structure and allow it to be tightly packaged. Histone modifiers control the accessibility of transcriptional machinery to the DNA. As such, they play a crucial role in the regulation of transcription of their target genes. Recent studies have reported a large number of mutations in genes encoding for histone modifiers in NHL. However, how they contribute to the development of cancer is unclear. The goal of my project is to understand how each of these mutations contributes to the development of NHL. I hypothesize that mutant histone modifiers target genes that control cell growth and proliferation. Alternatively, the mutations could foster self-renewal and prevent differentiation. My objectives are to 1) identify and characterize targets of mutant histone modifiers; 2) determine patterns of histone marks that are associated with the mutations; 3) examine if multiple mutations work together to promote cancer development. I will be developing and applying computational techniques to analyze high-throughput sequencing data from clinical DLBCL samples, and a range of mouse models and cell lines with a knock-in of the mutation of interest. Elucidating the mechanisms by which mutant histone modifiers contribute to cancer initiation and progression will help us better understand and predict how normal and diseased cells regulate their epigenomes. Our findings may uncover other druggable epigenetic factors that may lead to the development of novel therapies to impede their tumorigenic activities. Ultimately, we expect that our findings will result in more specific epigenetic therapeutic strategies for NHL patients, and offer the possibility of a better survival rate for this disease.

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