Ferroptosis is a form of cell death triggered by phospholipid hydroperoxides (PLOOH) generated from the iron-dependent oxidation of polyunsaturated fatty acids (PUFAs). To prevent ferroptosis, cells rely on the antioxidant glutathione (GSH), which serves as cofactor of the glutathione peroxidase 4 (GPX4) for the neutralization of PLOOHs. Some cancer cells can also limit ferroptosis through a GSH-independent axis, centered mainly on the ferroptosis suppressor protein 1 (FSP1). The significance of these two anti-ferroptosis pathways is still poorly understood in cancers from hematopoietic origin. Here, we report that blood-derived cancer cells are selectively sensitive to compounds that block the GSH-dependent anti-ferroptosis axis. In T- and B- acute lymphoblastic leukemia (ALL) cell lines and patient biopsies, the promoter of the gene coding for FSP1 is hypermethylated, silencing the expression of FSP1 and creating a selective dependency on GSH-centered anti-ferroptosis defenses. In-trans expression of FSP1 increases the resistance of leukemic cells to compounds targeting the GSH-dependent anti-ferroptosis pathway. FSP1 over-expression also favors ALL-tumor growth in an in vivo chick chorioallantoic membrane (CAM) model. Hence, our results reveal a metabolic vulnerability of ALL that might be of therapeutic interest.

铁死亡是由多不饱和脂肪酸 (PUFA) 铁依赖性氧化产生的磷脂氢过氧化物 (PLOOH) 引发的一种细胞死亡形式。为了防止铁死亡，细胞依赖抗氧化剂谷胱甘肽 (GSH)，它作为谷胱甘肽过氧化物酶 4 (GPX4) 的辅助因子来中和 PLOOH。一些癌细胞还可以通过一个不依赖于 GSH 的轴来限制铁死亡，该轴主要以铁死亡抑制蛋白 1 (FSP1) 为中心。这两种抗铁死亡途径的重要性在造血起源的癌症中仍然知之甚少。在这里，我们报告说，血液来源的癌细胞对阻断 GSH 依赖性抗铁死亡轴的化合物选择性敏感。在 T 和 B 急性淋巴细胞白血病 (ALL) 细胞系和患者活检中，编码 FSP1 的基因启动子高度甲基化，从而沉默 FSP1 的表达并产生对以 GSH 为中心的抗铁死亡防御的选择性依赖。FSP1 的反式表达增加了白血病细胞对针对 GSH 依赖性抗铁死亡途径的化合物的抵抗力。FSP1 过表达也有利于体内鸡绒毛尿囊膜 (CAM) 模型中的 ALL 肿瘤生长。因此，我们的结果揭示了 ALL 的代谢脆弱性，这可能具有治疗意义。