Session: 603. Lymphoid Oncogenesis: Basic: Poster I
Hematology Disease Topics & Pathways:
Research, Fundamental Science, Translational Research, Lymphomas, Non-Hodgkin lymphoma, B Cell lymphoma, Diseases, Aggressive lymphoma, Lymphoid Malignancies, Biological Processes, Molecular biology, Technology and Procedures, Gene editing
Interferon regulatory factor 2 binding protein 2 (IRF2BP2) is a transcriptional repressor that is frequently mutated in MCD patients, with many of these mutations predicted to be loss-of-function (Schmitz et al., 2018). Besides human DLBCL tumors, in previously published MCD mouse models, which harbor a B cell-specific loss of Prdm1, expression of mutant Myd88p.L252P, overexpression of BCL2, and in some cases expression of a Cd79b ITAM mutation, Irf2bp2 is also one of the most frequently co-mutated genes (Knittel et al., 2016, Flümann et al., 2023, Flümann et al., 2024). However, the role of IRF2BP2 in lymphoma biology and as a potential tumor suppressor gene in DLBCL has not been investigated.
To understand the role of IRF2BP2 in the germinal center reaction, we analyzed the B cell compartment of autochthonous mice which harbor a B cell specific knockout of Irf2bp2 at a premalignant age. We observed a dramatic decrease in germinal center B cells in Irf2bp2 knockout mice compared to controls, as well as a higher relative memory B cell output and reduced class switch recombination. This preliminary dataset suggests that Irf2bp2 may play a role in the dynamics of the germinal center reaction and B cell differentiation.
Moreover, we show that CRISPR/Cas9-mediated loss of IRF2BP2 in human ABC-DLBCL cell lines leads to increased proliferation and NF-KB signaling, compared to IRF2BP2-proficient cells. Additionally, we find that IRF2BP2 knockout ABC-DLBCL cells express higher interleukin-1 beta (IL1β) and are sensitive to anti-IL1β inhibition both in vitro and in vivo, while IRF2BP2-proficient cells remain insensitive. Furthermore, murine lymphoma cell lines derived from MCD mouse models, which harbor a spontaneous Irf2bp2 mutation are also sensitive to anti-IL1β inhibition in vitro and retain sensitivity over several weeks. Our findings suggest that IL1β is the primary mediator of increased NF-KB signaling upon IRF2BP2 perturbation and anti-IL1β therapy could be a potential treatment strategy for IRF2BP2-mutant patients.
Disclosures: Reinhardt: CDL Therapeutics GmbH: Current equity holder in private company; Gilead: Research Funding; Merck: Consultancy, Honoraria; Vertex: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Roche: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria.