Chronic lymphocytic leukemia cells are sensitive to the Apolipoprotein E-mediated disruption of metabolic homeostasis

Unraveling vulnerabilities in chronic lymphocytic leukemia (CLL) represents a key approach tounderstand molecular basis for its indolence and a path towards designing tailored therapeuticapproaches. We previously described that CLL cells are characterized by an ectopic expression ofthe immunomodulatory receptor ILT3/LILRB4. In this work, we found that CLL cells are particularlysensitive to the inhibitory action of the ILT3 ligand, an abundant serum apolipropotein E (ApoE).We find that, at physiological concentrations, ApoE inhibits CD40-driven proliferation of CLL cellsby interfering with two intrinsic CLL cell vulnerabilities. First, we find that ApoE is a copperbindingprotein that alters metal homeostasis of CLL cells and promotes copper-mediated cell death.Second, ApoE strongly downregulates D-3-phosphoglycerate dehydrogenase (PHGDH)-dependentbiosynthetic pathway, the activation of which is otherwise essential to support CLL proliferation.Escape from the ApoE-mediated inhibition is possible in the transformed CLL cells from patientswith Richter syndrome, which we link to the upregulation of PHGDH and the copper exporters ATP7Aand ATP7B. Finally, guided by single-cell data, we establish that primary stromal cells might bethe source of ApoE in the CLL bone marrow niche. Our findings suggest a natural ApoE-mediatedsuppression axis in CLL. Studying biochemical aspects of CLL regulation suggests that metabolicdisruption of cellular proliferation in tumor niches may control CLL cell proliferation, unlessopposed by tumor resistance in aggressive CLL.