Sensitivity to apolipoprotein E and copper poisoning as new therapeutic targets in chronic lymphocytic leukemia

Unraveling intrinsic vulnerabilities in chronic lymphocytic leukemia (CLL) represents a key approach to understand molecular basis for its indolence and a path towards developing treatments against CLL resistant to conventional therapy. In this work we establish that CLL cells are particularly sensitive to the inhibitory action of apolipropotein E (ApoE), an abundant serum protein regulating systemic lipid homeostasis. We find that, at physiological concentrations, ApoE inhibits proliferation of CLL cells by altering their metal homeostasis, with the contribution of copper toxicity. This finding guided us to discover that CLL cells are intrinsically sensitive to copper excess. A combination of ApoE and copper gives an optimal inhibitory profile to block proliferation of CLL cells. Our findings illustrate a new regulatory mechanism which may constitute a natural suppression mechanism targeting an intrinsic CLL vulnerability. ApoE-copper axis could be therapeutically explored by combining drugs that increase systemic levels of ApoE with copper coordination compounds to target CLL and other malignancies with similar sensitivit