文章：

自噬与泛素化协同下调B细胞急性淋巴细胞白血病中的癌蛋白E2A/Pbx1

Autophagy collaborates with ubiquitination to downregulate oncoprotein E2A/Pbx1 in B-cell acute lymphoblastic leukemia

原文发布日期：2015-01-23

DOI: 10.1038/bcj.2014.96

类型: Original Article

开放获取: 是

英文摘要：

B-cell acute lymphoblastic leukemia (B-ALL) accounts for the most cancer incidences in children. We present here that autophagy is downregulated in pediatric B-ALL, suggesting a possible link between autophagy failure and pediatric B-ALL leukemogenesis. With a pediatric t(1;19) B-ALL xenograft mouse model, we show here that activation of autophagy by preventive administration of rapamycin improved the survival of leukemia animals by partial restoration of hematopoietic stem/progenitor cells, whereas treatment of the animals with rapamycin caused leukemia bone marrow cell-cycle arrest. Activation of autophagy in vitro or in vivo by rapamycin or starvation downregulated oncogenic fusion protein E2A/Pbx1. Furthermore, E2A/Pbx1 was found to be colocalized with autophagy marker LC3 in autolysosomes and with ubiquitin in response to autophagy stimuli, whereas autophagy or ubiquitination inhibitor blocked these colocalizations. Together, our data suggest a collaborative action between autophagy and ubiquitination in the degradation of E2A/Pbx1, thereby revealing a novel strategy for targeted preventive or treatment therapy on the pediatric ALL.

摘要翻译： 

B细胞急性淋巴细胞白血病（B-ALL）是儿童中最常见的恶性肿瘤。本文发现自噬在儿童B-ALL中呈现下调趋势，提示自噬功能障碍与儿童B-ALL白血病发生可能存在关联。通过儿童t(1;19)易位B-ALL异种移植小鼠模型，我们发现预防性给予雷帕霉素激活自噬可部分恢复造血干/祖细胞，从而延长白血病动物的生存期；而治疗性使用雷帕霉素则会导致白血病骨髓细胞周期停滞。在体外或体内通过雷帕霉素或饥饿刺激激活自噬，均可下调致癌融合蛋白E2A/Pbx1的表达。进一步研究发现，在自噬激活条件下，E2A/Pbx1与自噬标记蛋白LC3在自溶酶体中共定位，并与泛素蛋白共聚集；而使用自噬抑制剂或泛素化抑制剂则可阻断这些共定位现象。我们的研究结果揭示了自噬与泛素化在降解E2A/Pbx1过程中存在协同作用，这为儿童ALL的靶向预防和治疗提供了新策略。

原文链接：

Autophagy collaborates with ubiquitination to downregulate oncoprotein E2A/Pbx1 in B-cell acute lymphoblastic leukemia