Apoliprotein E-mediated ferroptosis controls cellular proliferation in chronic lymphocytic leukemia

IF 12.8 1区 医学 Q1 HEMATOLOGY
Federica Nardi, Rosita Del Prete, Roberta Drago, Anthea Di Rita, Francesco Edoardo Vallone, Sara Ciofini, Margherita Malchiodi, Laura Pezzella, Laura Tinti, Vittoria Cicaloni, Laura Salvini, Danilo Licastro, Aidan T. Pezacki, Christopher J. Chang, Giuseppe Marotta, Antonella Naldini, Silvia Deaglio, Tiziana Vaisitti, Alessandro Gozzetti, Monica Bocchia, Anna Kabanova
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Abstract

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.

Abstract Image

脂蛋白 E 介导的铁蛋白沉积控制慢性淋巴细胞白血病的细胞增殖
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 细胞对丰富的血清蛋白载脂蛋白 E(ApoE)的抑制作用特别敏感。生理浓度的载脂蛋白E会影响CLL细胞的活力并抑制CD40驱动的细胞增殖。经载脂蛋白 E 处理的 CLL 细胞的转录组学显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内在机制。我们发现,一方面,载脂蛋白E处理的CLL细胞会诱导脂质过氧化和铁变态反应。另一方面,我们发现载脂蛋白是一种铜结合蛋白,细胞内的铜调节载脂蛋白的毒性。在侵袭性 CLL 中,ApoE 的调节作用往往会丧失。来自高白细胞计数患者的CLL细胞对载脂蛋白抑制的敏感性较低,而来自里克特综合征(RS)患者的转化型CLL细胞则可能对载脂蛋白产生抗性。尽管如此,侵袭性 CLL 和 RS 细胞都能保持对药物诱导的铁蛋白沉着的敏感性。我们的研究结果表明,一种自然抑制轴介导了铁蛋白沉积对 CLL 细胞增殖的破坏,从而为选择铁蛋白沉积作为 CLL 和 RS 的治疗靶点提供了依据。
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来源期刊
Leukemia
Leukemia 医学-血液学
CiteScore
18.10
自引率
3.50%
发文量
270
审稿时长
3-6 weeks
期刊介绍: Title: Leukemia Journal Overview: Publishes high-quality, peer-reviewed research Covers all aspects of research and treatment of leukemia and allied diseases Includes studies of normal hemopoiesis due to comparative relevance Topics of Interest: Oncogenes Growth factors Stem cells Leukemia genomics Cell cycle Signal transduction Molecular targets for therapy And more Content Types: Original research articles Reviews Letters Correspondence Comments elaborating on significant advances and covering topical issues
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