几十年来，核苷类似物的诱导治疗，特别是阿糖胞苷 (Ara-C) 和较小程度的氟达拉滨，一直是诊断为急性髓系白血病 (AML) 患者的标准治疗方法。尽管如此，核苷类似物的抗肿瘤功效常常受到内在和获得性耐药性的限制，从而导致治疗反应不佳和临床结果不佳。在这里，我们使用基于 CRISPR 的全基因组药物基因组筛选来绘制调节 AML 中核苷类似物反应的遗传因子，并确定 E3 泛素连接酶 Herc1 是 MLL/AF9 中 Ara-C 反应的关键调节剂 (MA)以及 HOXA9/MEIS1 (HM) 小鼠 AML 体外和体内模型。 HERC1 的缺失会损害细胞周期进程，从而增强小鼠和人类 AML 细胞系中核苷类似物诱导的细胞死亡。深入的蛋白质组学分析和随后的验证确定脱氧胞苷激酶 Dck 是 MA 和 HM 鼠细胞中 Herc1 的新靶标。我们观察到，与其他癌症类型相比，HERC1 在 AML 中过度表达，并且较高的 HERC1 表达与 TCGA 和 BEAT-AML 队列中 AML 患者的总生存期较短相关。总的来说，这项研究强调了 HERC1 在 AML 细胞对核苷类似物反应中的重要性，从而确立了这种 E3 泛素连接酶作为 AML 治疗的新型预测生物标志物和潜在治疗靶点。版权所有 © 2024 美国血液学会。

For several decades, induction therapy with nucleoside analogs, in particular cytarabine (Ara-C) and, to a lesser extent, fludarabine, has been the standard of care for patients diagnosed with acute myeloid leukemia (AML). Still, the anti-tumor efficacy of nucleoside analogs is often limited by intrinsic and acquired drug resistance, thereby leading to poor therapeutic response and suboptimal clinical outcomes. Here, we used genome-wide CRISPR-based pharmacogenomic screening to map the genetic factors that modulate the response to nucleoside analogs in AML and identified the E3 ubiquitin ligase Herc1 as a key modulator of Ara-C response in the MLL/AF9 (MA) and the HOXA9/MEIS1 (HM) murine AML models both in vitro and in vivo. Loss of HERC1 enhanced nucleoside analog-induced cell death in both murine and human AML cell lines by compromising cell cycle progression. In-depth proteomic analysis and subsequent validation identified deoxycytidine kinase Dck as a novel target of Herc1 in MA and HM murine cells. We observed that HERC1 is overexpressed in AML compared to other cancer types and higher HERC1 expression is associated with shorter overall survival of patients with AML in the TCGA and BEAT-AML cohorts. Collectively, this study highlights the importance of HERC1 in the response of AML cells to nucleoside analogs, thereby establishing this E3 ubiquitin ligase as a novel predictive biomarker and potential therapeutic target for the treatment of AML.Copyright © 2024 American Society of Hematology.