Ito Jumpei, Yamagata Kazutsune, Shinohara Haruka, Shima Yutaka, Katsumoto Takuo, Aikawa Yukiko, Kitabayashi Issay
Division of Hematological Malignancy, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.
Int J Hematol. 2023 Jan;117(1):78-89. doi: 10.1007/s12185-022-03469-8. Epub 2022 Oct 24.
Disease-risk stratification and development of intensified chemotherapy protocols have substantially improved the outcome of acute lymphoblastic leukemia (ALL). However, outcomes of relapsed or refractory cases remain poor. Previous studies have discussed the oncogenic role of enhancer of zeste homolog 1 and 2 (EZH1/2), and the efficacy of dual inhibition of EZH1/2 as a treatment for hematological malignancy. Here, we investigated whether an EZH1/2 dual inhibitor, DS-3201 (valemetostat), has antitumor effects on B cell ALL (B-ALL). DS-3201 inhibited growth of B-ALL cell lines more significantly and strongly than the EZH2-specific inhibitor EPZ-6438, and induced cell cycle arrest and apoptosis in vitro. RNA-seq analysis to determine the effect of DS-3201 on cell cycle arrest-related genes expressed by B-ALL cell lines showed that DS-3201 upregulated CDKN1C and TP53INP1. CRIPSR/Cas9 knockout confirmed that CDKN1C and TP53INP1 are direct targets of EZH1/2 and are responsible for the antitumor effects of DS-3201 against B-ALL. Furthermore, a patient-derived xenograft (PDX) mouse model showed that DS-3201 inhibited the growth of B-ALL harboring MLL-AF4 significantly. Thus, DS-3201 provides another option for treatment of B-ALL.
疾病风险分层和强化化疗方案的发展显著改善了急性淋巴细胞白血病（ALL）的治疗结果。然而，复发或难治性病例的治疗结果仍然很差。先前的研究已经讨论了zeste同源物1和2（EZH1/2）增强子的致癌作用，以及双重抑制EZH1/2作为血液系统恶性肿瘤治疗方法的疗效。在这里，我们研究了EZH1/2双重抑制剂DS-3201（瓦美司他）对B细胞ALL（B-ALL）是否具有抗肿瘤作用。与EZH2特异性抑制剂EPZ-6438相比，DS-3201更显著且强烈地抑制了B-ALL细胞系的生长，并在体外诱导细胞周期停滞和凋亡。RNA测序分析用于确定DS-3201对B-ALL细胞系表达的细胞周期停滞相关基因的影响，结果显示DS-3201上调了CDKN1C和TP53INP1。CRIPSR/Cas9基因敲除证实CDKN1C和TP53INP1是EZH1/2的直接靶点，并介导了DS-3201对B-ALL的抗肿瘤作用。此外，患者来源的异种移植（PDX）小鼠模型显示，DS-3201显著抑制了携带MLL-AF4的B-ALL的生长。因此，DS-3201为B-ALL的治疗提供了另一种选择。
