Mitotic perturbation is a key mechanism of action of decitabine in myeloid tumor treatment
Mitotic perturbation is a key mechanism of action of decitabine in myeloid tumor treatment
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DOI：
10.1016/j.celrep.2023.113098
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发表时间：
2023-09-26
期刊：
影响因子：
8.8
通讯作者：
Goyama，Susumu
中科院分区：
文献类型：
--
作者：
Yabushita，Tomohiro;Chinen，Takumi;Goyama，Susumu
地西他滨（DAC）是临床上用于治疗骨髓增生异常综合征（MDS）和急性髓细胞白血病（AML）的药物。我们使用MDS衍生的AML细胞进行的全基因组CRISPR-dCas 9活化筛选表明，有丝分裂调节对于DAC抗性至关重要。DAC在临床浓度下强烈诱导人类骨髓肿瘤的异常有丝分裂（分裂失败或三极有丝分裂），特别是在TP 53突变或既往血液学疾病的患者中。这种DAC诱导的有丝分裂破坏和凋亡在DNMT 1缺失的细胞中显著减弱。相反，Dnmt 1的过表达，而不是催化失活突变体，增强了骨髓肿瘤中DAC诱导的有丝分裂缺陷。我们还证明，DAC诱导的有丝分裂破坏增强了ATR-CLSPN-CHK 1途径的药理学抑制。这些数据挑战了当前的假设，即DAC通过DNMT 1抑制和随后的DNA低甲基化抑制白血病发生，并突出了DAC通过异常DNMT 1-DNA共价键破坏有丝分裂的有效活性。
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 withTP53mutations 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.