2. Academic Validation
  3. Piribedil disrupts the MLL1-WDR5 interaction and sensitizes MLL-rearranged acute myeloid leukemia (AML) to doxorubicin-induced apoptosis

Piribedil disrupts the MLL1-WDR5 interaction and sensitizes MLL-rearranged acute myeloid leukemia (AML) to doxorubicin-induced apoptosis

  • Cancer Lett. 2018 Sep 1;431:150-160. doi: 10.1016/j.canlet.2018.05.034.
Xiong Zhang 1,  Xingling Zheng 2,  Hong Yang 3,  Juan Yan 3,  Xuhong Fu 3,  Rongrui Wei 3,  Xiaowei Xu 3,  Zhuqing Zhang 3,  Aisong Yu 3,  Kaixin Zhou 3,  Jian Ding 4,  Meiyu Geng 5,  Xun Huang 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing, 210023, China.
  • 2 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing, 100049, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
  • 3 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing, 100049, China.
  • 4 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing, 210023, China; Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing, 100049, China. Electronic address: jding@simm.ac.cn.
  • 5 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing, 100049, China. Electronic address: mygeng@simm.ac.cn.
  • 6 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing, 100049, China. Electronic address: xhuang@simm.ac.cn.
PMID: 29857126 DOI: 10.1016/j.canlet.2018.05.034
Abstract

Targeting WT MLL for the treatment of MLL-r leukemia, which is highly aggressive and resistant to chemotherapy, has been shown to be a promising strategy. However, drug treatments targeting WT MLL are lacking. We used an in vitro Histone Methyltransferase assay to screen a library consists of 592 FDA-approved drugs for MLL1 inhibitors by measuring alterations in HTRF signal and found that Piribedil represented a potent activity. Piribedil specifically inhibited the proliferation of MLL-r cells by inducing cell-cycle arrest, Apoptosis and myeloid differentiation with little toxicity to the non-MLL cells. Mechanism study showed Piribedil blocked the MLL1-WDR5 interaction and thus selectively reduced MLL1-dependent H3K4 methylation. Importantly, MLL1 depletion induced gene expression that was similar to that induced by Piribedil and rendered the MLL-r cells resistant to Piribedil-induced toxicity, revealing Piribedil exerted anti-leukemia effects by targeting MLL1. Furthermore, both the Piribedil treatment and MLL1 depletion sensitized the MLL-r cells to doxorubicin-induced Apoptosis. Our study support the hypothesis that Piribedil could serve as a new drug for the treatment of MLL-r AML and provide new insight for further optimization of targeting MLL1 HMT activity.

Keywords

Apoptosis; Cell cycle; H3K4 methylation; MLL leukemia; Piribedil.

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