Inhibition of GATE-16 attenuates ATRA-induced neutrophil differentiation of APL cells and interferes with autophagosome formation.
Inhibition of GATE-16 attenuates ATRA-induced neutrophil differentiation of APL cells and interferes with autophagosome formation.
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DOI：
10.1016/j.bbrc.2013.07.056
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发表时间：
2013-08-23
影响因子：
3.1
通讯作者：
Tschan MP
中科院分区：
文献类型：
--
作者：
Brigger D;Torbett BE;Chen J;Fey MF;Tschan MP
自噬是一种细胞内大量降解过程，参与应激诱导后的细胞存活，但也具有新发现的髓样分化功能。自噬相关（ATG）8蛋白家族，包括GABARAP和LC 3亚家族，对自噬体的生物发生至关重要。为了评估GABARAPs在急性髓性白血病发病机制中的意义，我们比较了它们在原发性AML患者样品、CD 34+祖细胞和来自健康供体的粒细胞中的表达。与正常粒细胞相比，GABARAPL 1和GABARAPL 2/GATE-16在特定AML亚型中显著下调，但GABARAP没有。此外，GABARAPL 1和GATE-16的表达在ATRA诱导的急性早幼粒细胞白血病细胞的中性粒细胞分化过程中被显著诱导。最后，敲低APL细胞中的GABARAPL 2/GATE-16减弱中性粒细胞分化并降低自噬通量。总之，GABARAPL 2/GATE-16低表达与未成熟髓性白血病表型相关，这些蛋白质是APL细胞中性粒细胞分化所必需的。
Autophagy is an intracellular bulk degradation process involved in cell survival upon stress induction, but also with a newly identified function in myeloid differentiation. The autophagy-related (ATG)8 protein family, including the GABARAP and LC3 subfamilies, is crucial for autophagosome biogenesis. In order to evaluate the significance of the GABARAPs in the pathogenesis of acute myeloid leukemia, we compared their expression in primary AML patient samples, CD34+ progenitor cells and in granulocytes from healthy donors. GABARAPL1 and GABARAPL2/GATE-16, but not GABARAP, were significantly downregulated in particular AML subtypes compared to normal granulocytes. Moreover, the expression of GABARAPL1 and GATE-16 was significantly induced during ATRA-induced neutrophil differentiation of acute promyelocytic leukemia cells. Lastly, knocking down GABARAPL2/GATE-16 in APL cells attenuated neutrophil differentiation and decreased autophagic flux. In conclusion, low GABARAPL2/GATE-16 expression is associated with an immature myeloid leukemic phenotype and these proteins are necessary for neutrophil differentiation of APL cells.