P604: CHRONIC LYMPHOCYTIC LEUKEMIA CELLS ARE SENSITIVE TO THE APOLIPOPROTEIN E-MEDIATED DISRUPTION OF METABOLIC HOMEOSTASIS

Background: Unraveling intrinsic vulnerabilities in chronic lymphocytic leukemia (CLL) represents a key approach to understand molecular basis for its indolence and a path towards designing tailored therapeutic approaches. We previously described that CLL cells are characterized by an ectopic expression of the immunomodulatory cell surface receptor ILT3/LILRB4 (Zurli et al. Blood 2017). Despite functional implications of ILT3 expression have not been fully elucidated, its selective presence on CLL B cells, but not healthy B cells, made us hypothesize that it might influence CLL biology in a considerable way. Recently, a new physiological ligand for ILT3 has been described as the apolipotrotein E (ApoE), an abundant serum protein regulating systemic lipid homeostasis. Aims: Encouraged by the evidence that ApoE is a natural ligand for ILT3, here we investigated the effect of ApoE on CLL cell fitness and the underlying mechanisms of its action. Methods: We expressed lipoprotein-associated recombinant ApoE and used it for in-depth biochemical, transcriptomics and functional in vitro investigation of primary CLL cells from CLL patients and the Richter syndrome xenoografts. Results: We find that, at physiological concentrations, ApoE inhibits CD40-driven proliferation of CLL cells by interfering with two intrinsic CLL cell vulnerabilities. First, we establish that ApoE is a copper-binding protein that alters metal homeostasis of CLL cells and promotes a copper-mediated cell death. Second, ApoE strongly downregulates D-3-phosphoglycerate dehydrogenase (PHGDH), the activity of which is essential to support CLL proliferation. Escape from the ApoE-mediated inhibition is possible in the transformed CLL cells from patients with Richter syndrome. Our fundings made us hypothesize that ApoE could exert its inhibitory effect upon CLL cells in proliferating centers in the tumor niche. Single-cell data suggest that ApoE could be expressed in the CLL microenvironment, and in fact we detected ApoE in the secretome of primary stromal cell cultures derived from the CLL bone marrow. Summary/Conclusion: Our findings suggest a natural suppression mechanism in CLL mediated by ApoE. This protein, serum-derived and locally produced ApoE, can inhibit tumour cell growth by disrupting CLL cells metabolic homeostasis. This vulnerability might be associated with intrinsic hypersensitivity of CLL cells to oxidative stress and their dependence on metabolic rewiring for cellular proliferation. Keywords: B cell chronic lymphocytic leukemia