Proton pump inhibitors selectively suppress MLL rearranged leukemia cells via disrupting MLL1-WDR5 protein-protein interaction
Proton pump inhibitors selectively suppress MLL rearranged leukemia cells via disrupting MLL1-WDR5 protein-protein interaction
复制标题
质子泵抑制剂通过破坏 MLL1-WDR5 蛋白-蛋白相互作用选择性抑制 MLL 重排白血病细胞
DOI：
10.1016/j.ejmech.2019.112027
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发表时间：
2020-02-15
影响因子：
6.7
通讯作者：
Guo, Xiao-Ke
中科院分区：
文献类型：
--
作者：
Chen, Wei-Lin;Li, Dong-Dong;Guo, Xiao-Ke
Genetic rearrangements of the mixed lineage leukemia (MLL) leading to oncogenic MLL-fusion proteins (MLL-FPs). MLL-FPs occur in about 10% of acute leukemias and are associated with dismal prognosis and treatment outcomes which emphasized the need for new therapeutic strategies. In present study, by a cell-based screening in-house compound collection, we disclosed that Rabeprazole specially inhibited the proliferation of leukemia cells harboring MLL-FPs with little toxicity to non-MLL cells. Mechanism study showed Rabeprazole down-regulated the transcription of MLL-FPs related Hox and Meis1 genes and effectively inhibited MLL1 H3K4 methyltransferase (HMT) activity in MV4-11 cells bearing MLL-AF4 fusion protein. Displacement of MLL1 probe from WDR5 protein suggested that Rabeprazole may inhibit MLL1 HMT activity through disturbing MLL1-WDR5 protein-protein interaction. Moreover, other proton pump inhibitors (PPIs) also indicated the inhibition activity of MLL1-WDR5. Preliminary SARs showed the structural characteristics of PPIs were also essential for the activities of MLL1-WDR5 inhibition. Our results indicated the drug reposition of PPIs for MLL-rearranged leukemias and provided new insight for further optimization of targeting MLL1 methyltransferase activity, the MLL1-WDR5 interaction or WDR5. (C) 2020 Elsevier Masson SAS. All rights reserved.
