Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland.
Biochem Biophys Res Commun. 2013 Aug 23;438(2):283-8. doi: 10.1016/j.bbrc.2013.07.056. Epub 2013 Jul 24.
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 (AML), 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 (APL). 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.
自噬是一种细胞内的批量降解过程，涉及到细胞在应激诱导下的存活，但也有新发现的在髓系分化中的功能。自噬相关（ATG）8 蛋白家族，包括 GABARAP 和 LC3 亚家族，对于自噬体的生物发生至关重要。为了评估 GABARAP 在急性髓系白血病（AML）发病机制中的意义，我们比较了它们在原发性 AML 患者样本、CD34+祖细胞和健康供者的粒细胞中的表达。与正常粒细胞相比，GABARAPL1 和 GABARAPL2/GATE-16，但不是 GABARAP，在特定的 AML 亚型中显著下调。此外，在 ATRA 诱导急性早幼粒细胞白血病（APL）细胞向中性粒细胞分化过程中，GABARAPL1 和 GATE-16 的表达显著诱导。最后，在 APL 细胞中敲低 GABARAPL2/GATE-16 会减弱中性粒细胞分化并减少自噬通量。总之，GABARAPL2/GATE-16 的低表达与不成熟的髓系白血病表型相关，这些蛋白对于 APL 细胞的中性粒细胞分化是必需的。
