PU.1 is linking the glycolytic enzyme HK3 in neutrophil differentiation and survival of APL cells
PU.1 is linking the glycolytic enzyme HK3 in neutrophil differentiation and survival of APL cells
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DOI：
10.1182/blood-2011-09-378117
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发表时间：
2012-05-24
期刊：
影响因子：
20.3
通讯作者：
Tschan, Mario P.
中科院分区：
文献类型：
--
作者：
Federzoni, Elena A.;Valk, Peter J. M.;Tschan, Mario P.
转录因子PU.1是骨髓分化和功能的主要调节因子。另一方面，只有稀缺的信息是PU.1调节基因参与细胞存活。我们现在确定了糖酵解酶己糖激酶3（HK 3），一个具有细胞保护功能的基因，作为PU.1的转录靶点。有趣的是，HK 3表达与髓系细胞高度相关，并且与正常粒细胞相比，在急性髓系白血病患者中HK 3表达显著降低。此外，与非APL患者样本相比，急性早幼粒细胞白血病（APL）中HK 3表达显著降低。与在原发性APL患者样品中的观察一致，我们观察到在APL细胞系的中性粒细胞分化期间显著更高的HK 3表达。此外，敲低PU.1在中性粒细胞分化过程中损害HK 3诱导。发现PU.1和PML-RARA与HK 3启动子的体内结合，并且PML-RARA减弱了PU.1对HK 3启动子的激活。接下来，与对照细胞相比，抑制APL细胞系中的HK 3导致中性粒细胞分化和活力显著降低。我们的研究结果强烈表明，HK 3是：（1）直接激活的PU.1，（2）抑制PML-RARA，和（3）功能参与中性粒细胞分化和APL细胞的细胞活力。（血。2012;119（21）：4963-4970）
The transcription factor PU.1 is a master regulator of myeloid differentiation and function. On the other hand, only scarce information is available on PU.1-regulated genes involved in cell survival. We now identified the glycolytic enzyme hexokinase 3 (HK3), a gene with cytoprotective functions, as transcriptional target of PU.1. Interestingly, HK3 expression is highly associated with the myeloid lineage and was significantly decreased in acute myeloid leukemia patients compared with normal granulocytes. Moreover, HK3 expression was significantly lower in acute promyelocytic leukemia (APL) compared with non-APL patient samples. In line with the observations in primary APL patient samples, we observed significantly higher HK3 expression during neutrophil differentiation of APL cell lines. Moreover, knocking down PU.1 impaired HK3 induction during neutrophil differentiation. In vivo binding of PU.1 and PML-RARA to the HK3 promoter was found, and PML-RARA attenuated PU.1 activation of the HK3 promoter. Next, inhibiting HK3 in APL cell lines resulted in significantly reduced neutrophil differentiation and viability compared with control cells. Our findings strongly suggest that HK3 is: (1) directly activated by PU.1, (2) repressed by PML-RARA, and (3) functionally involved in neutrophil differentiation and cell viability of APL cells. (Blood. 2012;119(21):4963-4970)