Distinct Response Patterns to PHB Modulators in B Cell Lymphoma Models

Abstract

B cell malignancies, including chronic lymphocytic leukemia (CLL) and diffuse large B cell lymphoma (DLBCL), rely on dysregulated B cell receptor (BCR) signaling for survival and proliferation. Prohibitin 1 and 2 (PHB1, PHB2) are multifunctional proteins involved in mitochondrial function, IgM-type BCR signaling and other key oncogenic pathways, making them potential therapeutic targets in lymphomas. Here, we assessed the effects of five PHB-targeting small molecules - FL3, Mel6, Mel56, IN44, and Fluorizoline - on lymphoma cell lines as proof-of-concept study. PHB transcript and protein quantities were differentially affected and distinct patterns of antiproliferative effects and viability were observed. Across cell models, FL3, Mel56, and Mel6 displayed strongest effects. FL3 and Mel56 exerted strong cytotoxic effects, while Mel6 primarily slowed proliferation. IN44 showed modest but selective cytotoxic effects in an ABC-DLBCL model, while Fluorizoline selectively stopped proliferation of a Burkitt lymphoma model. Non-malignant stromal cells remained largely unaffected by Mel56, highlighting a potential therapeutic window of this inhibitor. Replacing the native IgM constant region by IgG in the MEC-1 CLL line using CRISPR-Cas9 resulted in a somewhat reduced, but not abrogated effect of Mel56 suggesting effects on additional pathways beyond the BCR. Together these data provide proof-of-concept evidence for PHB inhibition as a potential strategy to target B cell lymphomas.