1] Experimental Oncology/Hematology, Department of Clinical Research, University of Bern, Bern, Switzerland [2] Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland [3] Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA [4].
1] Experimental Oncology/Hematology, Department of Clinical Research, University of Bern, Bern, Switzerland [2] Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland [3].
Sci Rep. 2014 Mar 3;4:4261. doi: 10.1038/srep04261.
The basic leucine zipper transcription factor CCAAT/enhancer binding protein alpha (CEBPA) codes for a critical regulator during neutrophil differentiation. Aberrant expression or function of this protein contributes to the development of acute myeloid leukemia (AML). In this study, we identified two novel unrelated CEBPA target genes, the glycolytic enzyme hexokinase 3 (HK3) and the krüppel-like factor 5 (KLF5) transcription factor, by comparing gene profiles in two cohorts of CEBPA wild-type and mutant AML patients. In addition, we found CEBPA-dependent activation of HK3 and KLF5 transcription during all-trans retinoic acid (ATRA) mediated neutrophil differentiation of acute promyelocytic leukemia (APL) cells. Moreover, we observed direct regulation of HK3 by CEBPA, whereas our data suggest an indirect regulation of KLF5 by this transcription factor. Altogether, our data provide an explanation for low HK3 and KLF5 expression in particular AML subtype and establish these genes as novel CEBPA targets during neutrophil differentiation.
碱性亮氨酸拉链转录因子 CCAAT/增强子结合蛋白α（CEBPA）在中性粒细胞分化过程中编码一种关键的调节因子。该蛋白的异常表达或功能导致急性髓细胞白血病（AML）的发生。在这项研究中，我们通过比较两组 CEBPA 野生型和突变型 AML 患者的基因谱，鉴定了两个新的不相关的 CEBPA 靶基因，即糖酵解酶己糖激酶 3（HK3）和 Krüppel 样因子 5（KLF5）转录因子。此外，我们发现全反式视黄酸（ATRA）介导的急性早幼粒细胞白血病（APL）细胞向中性粒细胞分化过程中，CEBPA 依赖性激活了 HK3 和 KLF5 的转录。此外，我们观察到 HK3 受 CEBPA 的直接调控，而我们的数据表明 KLF5 受该转录因子的间接调控。总之，我们的数据为特定 AML 亚型中 HK3 和 KLF5 表达水平低提供了一个解释，并将这两个基因确立为中性粒细胞分化过程中 CEBPA 的新靶基因。
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