PFKFB4 is critical for the survival of acute monocytic leukemia cells
PFKFB4 is critical for the survival of acute monocytic leukemia cells
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DOI：
10.1016/j.bbrc.2020.03.174
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发表时间：
2020-06-11
影响因子：
3.1
通讯作者：
Dong, Shasha
中科院分区：
文献类型：
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作者：
Wang, Gongai;Li, Shumei;Dong, Shasha
急性髓系白血病 (AML) 的特点是血细胞过度增殖，在成人和儿童中分为多种亚型。据报道，在这些亚型中，急性单核细胞白血病（M4/M5、AMoL）与导致单核细胞分化受阻的异常基因融合有关。然而，很少有研究表明细胞代谢与 AMoL 启动之间的关系。在这里，我们使用开放获取数据库TCGA来分析代谢循环中酶的表达，发现PFKFB4在AMoL中高表达。随后，敲低THP-1和U937细胞中的PFKFB4可显着抑制细胞生长并增加细胞对化学药物诱导的细胞凋亡的敏感性。与基因编辑改变一致，PFKFB4 抑制剂治疗对 THP-1 和 U937 增殖和凋亡表现出类似的效果。此外，我们发现 PFKFB4 作为表观遗传调节器 MLL 的可靠靶标，MLL 是 AMoL 中众所周知的调节器。从机制上讲，MLL 通过 pfkfb4 基因启动子中推定的 E2F6 结合位点在转录水平促进 PFKFB4 表达。综上所述，我们的结果表明 PFKFB4 作为 MLL 的下游靶点，并作为 AMoL 的有效治疗靶点。 (C) 2020 Elsevier Inc. 保留所有权利。
Acute myeloid leukemia (AML), which is characterized by an overproliferation of blood cells, is divided into several subtypes in adults and children. Of those subtypes, acute monocytic leukemia (M4/M5, AMoL) is reported to be associated with abnormal gene fusions that result in monocytic cell differentiation being blocked. However, few studies have shown a relationship between cellular metabolism and the initiation of AMoL. Here, we use the open-access database TCGA to analyze the expression of enzymes in the metabolic cycle and find that PFKFB4 is highly expressed in AMoL. Subsequently, knocking down PFKFB4 in THP-1 and U937 cells significantly inhibits cell growth and increases the sensitivity of cells to chemical drug-induced apoptosis. In line with the gene-editing alterations, treatment with a PFKFB4 inhibitor exhibits similar effects on THP-1 and U937 proliferation and apoptosis. In addition, we find that PFKFB4 functions as a reliable target of the epigenetic regulator MLL, which is a well-known modulator in AMoL. Mechanistically, MLL promotes PFKFB4 expression at the transcriptional level through the putative E2F6 binding site in the promoter of the pfkfb4 gene. Taken together, our results suggest PFKFB4 serves as a downstream target of MLL and functions as a potent therapeutic target in AMoL. (C) 2020 Elsevier Inc. All rights reserved.