LAUSR

DLBCL is the most common B cell malignancy in adults accounting for 30-40% of non-Hodgkin lymphoma. Only 60% of these cases are curable, with activated B cell DLBCL (ABC-DLBCL) having inferior outcomes than the germinal center (GCB) DLBCL. The use of ibrutinib to treat non-responsive/relapsed ABC-DLBCL cases has significantly improved the treatment of this disease. However, in more than 40% of ABC-DLBCL cases, the disease progresses or develops resistance to ibrutinib. Thus, there is an urgent unmet need to understand the molecular basis of resistance mechanisms and identify novel therapeutic regimens to treat IR DLBCL. Utilizing high throughput metabolomics, we identified cysteine-methionine metabolism and alanine, aspartate, and glutamate metabolism to be deregulated in IR cells. We further identified interleukin four induced 1 (IL4I1), an L-amino acid oxidase that partakes in cysteine and methionine metabolism by contributing to the methionine salvage pathway. The amino acid cysteine contributes to cancer metabolic remodeling by a), in its free form, in redox control, as a component of the antioxidant glutathione or its involvement in protein s-cysteinylation, b), as a substrate for the production of hydrogen sulfide (H2S), which feeds the mitochondrial electron transfer chain and mediates persulphidation of ATPase and glycolytic enzymes, thereby stimulating cellular bioenergetics; and, c), as a carbon source for epigenetic regulation, biomass production, and energy production. Consistent with this, we show that loss of IL4I1 expression induced aberrant cysteine and methionine metabolism accompanied by metabolic reprogramming to OXPHOS, which collectively enabled increased drug tolerance of DLBCL. This adaptive metabolic mechanism exhibited increased cysteine and cystathionine intracellular levels in IR-DLBCL lacking IL4I1 expression. As cysteine and glutathione are scavengers of free radicals (mainly reactive oxygen species (ROS)), they can nullify the effects of the majority of oxidative or alkylating drugs used in cancer therapy, affording a vital resistance mechanism and disruption of cysteine homeostasis appears to be promising strategy for induction of cancer cell death and provide therapeutic approaches to treat Ibrutinib-resistant-ABC- DLBCL for improved patient care. Citation Format: Satishkumar Singh, Fouad Choueiry, Anuvrat Sircar, Narendranath Epperla, Jiangjiang Zhu, Lalit Sehgal. Uncovering the metabolic vulnerabilities in activated B cell diffuse large B cell lymphoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3689.