Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland.
Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
Sci Rep. 2017 Oct 11;7(1):12980. doi: 10.1038/s41598-017-12734-4.
Acute myeloid leukemia (AML) is a malignancy of myeloid progenitor cells that are blocked in differentiation. Acute promyelocytic leukemia (APL) is a rare form of AML, which generally presents with a t(15;17) translocation causing expression of the fusion protein PML-RARA. Pharmacological doses of all-trans retinoic acid (ATRA) induce granulocytic differentiation of APL cells leading to cure rates of >80% if combined with conventional chemotherapy. Autophagy is a lysosomal degradation pathway for the removal of cytoplasmic content and recycling of macromolecules. ATRA induces autophagy in ATRA-sensitive AML and APL cells and autophagy inhibition attenuates ATRA-triggered differentiation. In this study, we aimed at identifying if the autophagy-linked FYVE-domain containing protein (ALFY/WDFY3) is involved in autophagic degradation of protein aggregates contributes to ATRA therapy-induced autophagy. We found that ALFY mRNA levels increase significantly during the course of ATRA-induced differentiation of APL and AML cell lines. Importantly ALFY depletion impairs ATRA-triggered granulocytic differentiation of these cells. In agreement with its function in aggrephagy, knockdown of ALFY results in reduced ATRA-induced proteolysis. Our data further suggest that PML-RARα is an autophagy substrate degraded with the help of ALFY. In summary, we present a crucial role for ALFY in retinoid triggered maturation of AML cells.
急性髓系白血病（AML）是一种骨髓祖细胞恶性肿瘤，其分化受阻。急性早幼粒细胞白血病（APL）是一种罕见的 AML 形式，通常表现为 t(15;17)易位导致融合蛋白 PML-RARA 的表达。全反式维甲酸（ATRA）的药理剂量诱导 APL 细胞的粒细胞分化，如果与常规化疗联合使用，治愈率>80%。自噬是一种溶酶体降解途径，用于去除细胞质内容物和回收大分子。ATRA 在 ATRA 敏感的 AML 和 APL 细胞中诱导自噬，并且自噬抑制减弱 ATRA 触发的分化。在这项研究中，我们旨在确定自噬相关 FYVE 结构域蛋白（ALFY/WDFY3）是否参与蛋白聚集体的自噬降解，从而有助于 ATRA 治疗诱导的自噬。我们发现，在 ATRA 诱导的 APL 和 AML 细胞系分化过程中，ALFY mRNA 水平显著增加。重要的是，ALFY 耗竭会损害这些细胞的 ATRA 触发的粒细胞分化。与它在聚集物自噬中的功能一致，ALFY 的敲低导致 ATRA 诱导的蛋白水解减少。我们的数据进一步表明，PML-RARα 是一种在 ALFY 帮助下降解的自噬底物。总之，我们提出了 ALFY 在视黄酸触发 AML 细胞成熟中的关键作用。
