Involvement of prohibitins in an oncogenic protein complex in Chronic Lymphocytic Leukemia

Abstract Prohibitins (PHB1 and PHB2) are highly conserved and ubiquitously expressed proteins that are mainly localized in the mitochondria. They have been reported to have multiple functions, which can vary depending on their cellular localization and cell type. They are implicated in several critical cellular processes, including proliferation, functional integrity of mitochondria, cell survival, and apoptosis. Recently, research has highlighted the potential role of prohibitins in cancer pathogenesis, notably in some hematological malignancies. However, their mechanisms of action remain largely misunderstood. In this study, we report the involvement of prohibitins in a previously identified oncogenic protein complex in Chronic Lymphocytic Leukemia (CLL) involving NTSR2, a low-affinity G protein-coupled receptor for neurotensin, and TrkB, a receptor for brain-derived neurotrophic factor (BDNF). We evidenced the overexpression of prohibitins in CLL patients B cells compared to healthy donors PBMCs and demonstrated the interaction of PHB1 and PHB2 with the oncogenic protein complex. We also showed that prohibitins regulate NTSR2 expression, potentially via its interaction with transcription factors and that selective prohibitin inhibition affects downstream NTSR2/TrkB signaling. Overall, these findings suggest a role of prohibitins in CLL pathogenesis and their potential as disease biomarkers or therapeutic targets.