Date of Award

2021

Degree Name

Biomedical Sciences

College

Joan C. Edwards School of Medicine

Type of Degree

Ph.D.

Document Type

Dissertation

First Advisor

Dr. Philippe Georgel, Committee Chairperson

Second Advisor

Dr. Piyali Dasgupta

Third Advisor

Dr. Richard Egleton

Fourth Advisor

Dr. Doreen Griswold

Fifth Advisor

Dr. Travis Salisbury

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma. It is an aggressive cancer, with 50-70% of patients diagnosed at an advanced stage and 30-50% of patients not cured by chemoimmunotherapy. DLBCL is almost always caused by genetic damage sustained during the germinal center (GC) reaction. The mechanisms that govern the GC reaction bear a striking resemblance to those that drive DLBCL. Genomic studies have shown that some of its most common mutations occur in genes that encode epigenetic modifiers, including the lysine (histone) acetyltransferases CREBBP and p300. These mutations prevent the acetylation of multiple histone residues, including H3K27Ac (activating) along the enhancers of genes whose expression is required for essential functions like GC exit and differentiation. CBP/p300 mutations also prevent the acetylation of p53 (activating) and BCL6 (inhibiting). In light of recent evidence that -3 fatty acids (-3 FA) can influence histone acetylation in cancer, we tested the ability of the -3 FA docosahexaenoic acid (DHA) to restore levels of histone and p53 acetylation in three DLBCL cell lines (with different CREBBP/EP300 mutational statuses) and one line of normal B-cells. After exposure to DHA at clinically attainable doses, we observed significant changes in the genome-wide levels of histone post-translational modifications (PTMs) (including acetylated residues H3K9Ac, H4K5Ac, H4K8Ac, H4K12Ac, H4K16Ac) in a cell-line and dose-dependent manner. Histone acetylation did not uniformly increase as expected, but levels of p53 acetylation did. We also observed significant changes in the expression of relevant genes, such as increased expression of CREBBP and PRDM1; the latter is required for the differentiation of GC B-cells into plasma cells or memory B-cells. Overall, we have performed (to our knowledge) the first characterization of the epigenetic effects of -3 FA in DLBCL. Our results highlight their therapeutic potential and emphasize the need for further investigation.

Subject(s)

Lymphomas -- Genetic aspects -- Research.

Genomics -- Research.

Omega-3 fatty acids -- Research.

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