Unraveling vulnerabilities in chronic lymphocytic leukemia (CLL) represents a key approach to understand molecular basis for its indolence and a path toward developing tailored therapeutic approaches. In this study, we found that CLL cells are particularly sensitive to the inhibitory action of abundant serum protein, apolipoprotein E (ApoE). Physiological concentrations of ApoE affect CLL cell viability and inhibit CD40-driven proliferation. Transcriptomics of ApoE-treated CLL cells revealed a signature of redox and metal disbalance which prompted us to explore the underlying mechanism of cell death. We discover, on one hand, that ApoE treatment of CLL cells induces lipid peroxidation and ferroptosis. On the other hand, we find that ApoE is a copper-binding protein and that intracellular copper regulates ApoE toxicity. ApoE regulation tends to be lost in aggressive CLL. CLL cells from patients with high leukocyte counts are less sensitive to ApoE inhibition, while resistance to ApoE is possible in transformed CLL cells from patients with Richter syndrome (RS). Nevertheless, both aggressive CLL and RS cells maintain sensitivity to drug-induced ferroptosis. Our findings suggest a natural suppression axis that mediates ferroptotic disruption of CLL cell proliferation, building up the rationale for choosing ferroptosis as a therapeutic target in CLL and RS.

揭示慢性淋巴细胞白血病 （CLL） 的脆弱性是了解其惰性分子基础的关键方法，也是开发定制治疗方法的途径。在这项研究中，我们发现 CLL 细胞对丰度血清蛋白载脂蛋白 E （ApoE） 的抑制作用特别敏感。生理浓度的 ApoE 影响 CLL 细胞活力并抑制 CD40 驱动的增殖。ApoE 处理的 CLL 细胞的转录组学揭示了氧化还原和金属失衡的特征，这促使我们探索细胞死亡的潜在机制。我们发现，一方面，CLL 细胞的 ApoE 处理会诱导脂质过氧化和铁死亡。另一方面，我们发现 ApoE 是一种铜结合蛋白，细胞内铜调节 ApoE 毒性。ApoE 调节在侵袭性 CLL 中往往会丢失。来自白细胞计数高患者的 CLL 细胞对 ApoE 抑制的敏感性较低，而来自里氏综合征 （RS） 患者转化的 CLL 细胞可能对 ApoE 产生耐药性。然而，侵袭性 CLL 和 RS 细胞都对药物诱导的铁死亡保持敏感性。我们的研究结果表明，存在一种天然抑制轴，可介导 CLL 细胞增殖的铁死亡破坏，为选择铁死亡作为 CLL 和 RS 的治疗靶点奠定了基础。