Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Department of Pathology, NYU Grossman School of Medicine, New York, NY 10016, USA.
Cell Rep. 2023 Jan 31;42(1):112027. doi: 10.1016/j.celrep.2023.112027. Epub 2023 Jan 23.
TET2 haploinsufficiency is a driving event in myeloid cancers and is associated with a worse prognosis in patients with acute myeloid leukemia (AML). Enhancing residual TET2 activity using vitamin C increases oxidized 5-methylcytosine (mC) formation and promotes active DNA demethylation via base excision repair (BER), which slows leukemia progression. We utilize genetic and compound library screening approaches to identify rational combination treatment strategies to improve use of vitamin C as an adjuvant therapy for AML. In addition to increasing the efficacy of several US Food and Drug Administration (FDA)-approved drugs, vitamin C treatment with poly-ADP-ribosyl polymerase inhibitors (PARPis) elicits a strong synergistic effect to block AML self-renewal in murine and human AML models. Vitamin-C-mediated TET activation combined with PARPis causes enrichment of chromatin-bound PARP1 at oxidized mCs and γH2AX accumulation during mid-S phase, leading to cell cycle stalling and differentiation. Given that most AML subtypes maintain residual TET2 expression, vitamin C could elicit broad efficacy as a PARPi therapeutic adjuvant.
TET2 杂合性缺失是髓系肿瘤的驱动事件，与急性髓系白血病（AML）患者的预后不良相关。使用维生素 C 增强残留的 TET2 活性会增加氧化的 5-甲基胞嘧啶（mC）形成，并通过碱基切除修复（BER）促进活性 DNA 去甲基化，从而减缓白血病的进展。我们利用遗传和化合物文库筛选方法来确定合理的联合治疗策略，以提高维生素 C 作为 AML 辅助治疗的效果。除了增加几种美国食品和药物管理局（FDA）批准药物的疗效外，维生素 C 与聚 ADP-核糖聚合酶抑制剂（PARPi）联合治疗在小鼠和人类 AML 模型中表现出强烈的协同作用，可阻断 AML 自我更新。维生素 C 介导的 TET 激活与 PARPi 联合使用会导致氧化的 mC 上结合的 PARP1 和 γH2AX 在中期 S 期积累，导致细胞周期停滞和分化。鉴于大多数 AML 亚型仍保留残留的 TET2 表达，维生素 C 作为 PARPi 治疗佐剂可能具有广泛的疗效。
