Abstract B-cell lymphoma is a severe type of lymphatic cancer that is often misdiagnosed in adolescents. While some cases of B-cell lymphoma respond well to chemo- and radiation therapy, there are severe side effects, and many cases are refractory and fail to achieve remission. On the other hand, though CD19 CAR T-cell therapy is highly effective at treating B-cell lymphoma, its association with long-term immunocompromisation justifies the exploration of alternative treatments. Comparing B-cell lymphomas to an autoimmune disease that affects the same tissue type may grant us additional insights into immuno-oncology related treatments for B-cell lymphoma. We have developed a novel tool to compare cancer and autoimmune disease by analyzing bulk RNA-sequencing (RNA-seq) data. This algorithmic approach uses the transcriptional profile to improve our understanding of B-cell specific mechanisms that can be targeted in B-cell lymphoma. Using this tool, we compared the transcriptional signatures of primary B-cell lymphomas with primary B-cells from patients with systemic lupus erythematosus, an autoimmune disease. We identified specific genes and enriched functions associated with B-cell lymphoma’s immune signature. We expect that the results of our B-cell lymphoma analysis could be used to develop beneficial treatments alternative to current therapies, potentially mitigating side effects for B-cell lymphoma patients and increasing their quality of life. Citation Format: Sehi Kim, Naomi Rapier-Sharman, Michael T. Told, Kim L. O’Neill, Brett E. Pickett. Comparative transcriptomic analysis reveals novel insights into targetable B-cell lymphoma mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7357.