Zhao Min, Wang Jiangyun, Qu Mei, Zhao Yao, Wang Haihua, Ke Yu, Liu Ying, Lei Zi-Ning, Liu Hong-Min, Hu Zhenbo, Wei Liuya, Chen Zhe-Sheng
Laboratory for Stem Cell and Regenerative Medicine, Affiliated Hospital of Weifang Medical University, Weifang, China.
School of Pharmacy, Weifang Medical University, Weifang, China.
Front Cell Dev Biol. 2021 Mar 4;9:652972. doi: 10.3389/fcell.2021.652972. eCollection 2021.
Acute myelogenous leukemia (AML) is characterized by blockage of cell differentiation leading to the accumulation of immature cells, which is the most prevalent form of acute leukemia in adults. It is well known that all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) are the preferred drugs for acute promyelocytic leukemia (APL). However, they can lead to irreversible resistance which may be responsible for clinical failure after complete remission (CR). Moreover, the differentiation therapy of ATRA-based treatment has not been effective against AML with t(8;21) translocation. Here we aimed to identify the differentiation effect of OGP46 on AML cell lines (HL-60, NB4, and Kasumi-1) and explore its possible mechanisms. We found that OGP46 has significant inhibitory activity against these cells by triggering cell differentiation with cell-cycle exit at G1/G0 and inhibited the colony-formation capacity of the AML cells. It was shown that OGP46 induced the differentiation of NB4 cells via the transcriptional misregulation in cancer signaling pathway by PML-RARα depletion, while it was attributed to the hematopoietic cell lineage and phagosome pathway in Kasumi-1 cells, which are all critical pathways in cell differentiation. These results highlight that OGP46 is an active agent not only in the APL cell line NB4 but also in AML-M2 cell lines, especially Kasumi-1 with t(8;21) translocation. Therefore, OGP46 may be a potential compound for surmounting the differentiation blockage in AML.
急性髓系白血病（AML）的特征是细胞分化受阻，导致未成熟细胞积累，这是成人急性白血病最常见的形式。众所周知，全反式维甲酸（ATRA）和三氧化二砷（ATO）是急性早幼粒细胞白血病（APL）的首选药物。然而，它们可导致不可逆的耐药性，这可能是完全缓解（CR）后临床失败的原因。此外，基于ATRA的分化疗法对伴有t(8;21)易位的AML无效。在这里，我们旨在确定OGP46对AML细胞系（HL-60、NB4和Kasumi-1）的分化作用，并探讨其可能的机制。我们发现，OGP46通过触发细胞在G1/G0期退出细胞周期而诱导细胞分化，从而对这些细胞具有显著的抑制活性，并抑制了AML细胞的集落形成能力。结果表明，OGP46通过PML-RARα缺失导致癌症信号通路中的转录失调来诱导NB4细胞分化，而在Kasumi-1细胞中，这归因于造血细胞谱系和吞噬体途径，这些都是细胞分化中的关键途径。这些结果表明，OGP46不仅在APL细胞系NB4中，而且在AML-M2细胞系中，尤其是在伴有t(8;21)易位的Kasumi-1细胞系中，都是一种活性剂。因此，OGP46可能是一种克服AML分化阻滞的潜在化合物。
