有丝分裂的紊乱是脱氧胞苷在髓系肿瘤治疗中的关键作用机制。
Mitotic perturbation is a key mechanism of action of decitabine in myeloid tumor treatment.
发表日期：2023 Sep 12
作者：
Tomohiro Yabushita, Takumi Chinen, Atsuya Nishiyama, Shuhei Asada, Ruka Shimura, Tomoya Isobe, Keita Yamamoto, Naru Sato, Yutaka Enomoto, Yosuke Tanaka, Tomofusa Fukuyama, Hitoshi Satoh, Keiko Kato, Kaori Saitoh, Takamasa Ishikawa, Tomoyoshi Soga, Yasuhito Nannya, Tatsuo Fukagawa, Makoto Nakanishi, Daiju Kitagawa, Toshio Kitamura, Susumu Goyama
来源：
Cell Reports
摘要：
Decitabine (DAC)是临床上用于治疗骨髓增生异常综合征(MDS)和急性髓系白血病(AML)的药物。我们使用MDS来源的AML细胞进行基因组范围的CRISPR-dCas9激活筛选试验，结果显示有丝分裂调节对DAC耐药性至关重要。DAC在临床浓度下能够强烈引发人类髓系肿瘤中的异常有丝分裂(分离失败或三极分裂)，尤其是在具有TP53突变或之前存在造血系统疾病的患者中。在DNMT1受损细胞中，DAC诱导的有丝分裂紊乱和凋亡显著减弱。相反，Dnmt1的过表达(而非无催化活性突变体)增强了DAC在髓系肿瘤中引发的有丝分裂缺陷。我们还证明DAC诱导的有丝分裂紊乱受到ATR-CLSPN-CHK1途径药物抑制的影响。这些数据挑战了DAC通过DNMT1抑制和随后的DNA低甲基化抑制白血病发生的当前假设，并突显了DAC通过异常的DNMT1-DNA共价键干扰有丝分裂的强大活性。Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
Decitabine (DAC) is clinically used to treat myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Our genome-wide CRISPR-dCas9 activation screen using MDS-derived AML cells indicates that mitotic regulation is critical for DAC resistance. DAC strongly induces abnormal mitosis (abscission failure or tripolar mitosis) in human myeloid tumors at clinical concentrations, especially in those with TP53 mutations or antecedent hematological disorders. This DAC-induced mitotic disruption and apoptosis are significantly attenuated in DNMT1-depleted cells. In contrast, overexpression of Dnmt1, but not the catalytically inactive mutant, enhances DAC-induced mitotic defects in myeloid tumors. We also demonstrate that DAC-induced mitotic disruption is enhanced by pharmacological inhibition of the ATR-CLSPN-CHK1 pathway. These data challenge the current assumption that DAC inhibits leukemogenesis through DNMT1 inhibition and subsequent DNA hypomethylation and highlight the potent activity of DAC to disrupt mitosis through aberrant DNMT1-DNA covalent bonds.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.