Centre for Molecular Biology and Neuroscience (CMBN) and Institute of Medical Microbiology, Rikshospitalet University Hospital, and Institute of Clinical Biochemistry, University of Oslo, Oslo, Norway.
Autophagy. 2010 Oct;6(7):964-5. doi: 10.4161/auto.6.7.13066. Epub 2010 Oct 19.
Acute promyelocytic leukemia (APL) is characterized by a chromosomal t(15;17) translocation that fuses the gene encoding the promyelocytic leukemia protein (PML) to that encoding retinoic acid receptor alpha (RARA). The product of this genetic aberration, the PML/RARA fusion protein, is highly oncogenic and supports malignant transformation and growth of hematopoietic precursor cells at the promyelocytic stage of differentiation. Successful treatment of APL by all-trans retinoic acid (ATRA) or arsenic trioxide (ATO) depends on the ability of these drugs to induce proteolytic degradation of this chimeric protein. In a recently published study we demonstrate that PML/RARA is amenable for degradation by autophagy and that ATRA- and ATO-induced PML/RARA degradation is autophagy-dependent. Consequently, autophagic degradation regulates basal turnover as well as therapy-induced elimination of this oncoprotein. In addition, our study reveals an important role of autophagy in promoting granulocytic differentiation of APL cells.
急性早幼粒细胞白血病（APL）的特征是存在染色体 t（15；17）易位，该易位将编码早幼粒细胞白血病蛋白（PML）的基因与编码维甲酸受体 alpha（RARA）的基因融合。这种遗传异常的产物，即 PML/RARA 融合蛋白，具有高度致癌性，并支持造血前体细胞在早幼粒细胞分化阶段的恶性转化和生长。全反式维甲酸（ATRA）或三氧化二砷（ATO）成功治疗 APL 取决于这些药物诱导这种嵌合蛋白蛋白水解降解的能力。在最近发表的一项研究中，我们证明 PML/RARA 可通过自噬降解，并且 ATRA 和 ATO 诱导的 PML/RARA 降解是自噬依赖性的。因此，自噬降解调节这种癌蛋白的基础周转率以及治疗诱导的消除。此外，我们的研究揭示了自噬在促进 APL 细胞粒细胞分化中的重要作用。
