Orfali Nina, O'Donovan Tracey R, Nyhan Michelle J, Britschgi Adrian, Tschan Mario P, Cahill Mary R, Mongan Nigel P, Gudas Lorraine J, McKenna Sharon L
Cork Cancer Research Centre, Leslie C. Quick, Jr., Laboratory, Biosciences Institute, University College Cork, Cork, Ireland; Department of Hematology, Cork University Hospital, Cork, Ireland; Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA.
Cork Cancer Research Centre, Leslie C. Quick, Jr., Laboratory, Biosciences Institute, University College Cork, Cork, Ireland.
Exp Hematol. 2015 Sep;43(9):781-93.e2. doi: 10.1016/j.exphem.2015.04.012. Epub 2015 May 16.
Acute myeloid leukemia (AML) is characterized by the accumulation of immature blood cell precursors in the bone marrow. Pharmacologically overcoming the differentiation block in this condition is an attractive therapeutic avenue, which has achieved success only in a subtype of AML, acute promyelocytic leukemia (APL). Attempts to emulate this success in other AML subtypes have thus far been unsuccessful. Autophagy is a conserved protein degradation pathway with important roles in mammalian cell differentiation, particularly within the hematopoietic system. In the study described here, we investigated the functional importance of autophagy in APL cell differentiation. We found that autophagy is increased during all-trans-retinoic acid (ATRA)-induced granulocytic differentiation of the APL cell line NB4 and that this is associated with increased expression of LC3II and GATE-16 proteins involved in autophagosome formation. Autophagy inhibition, using either drugs (chloroquine/3-methyladenine) or short-hairpin RNA targeting the essential autophagy gene ATG7, attenuates myeloid differentiation. Importantly, we found that enhancing autophagy promotes ATRA-induced granulocytic differentiation of an ATRA-resistant derivative of the non-APL AML HL60 cell line (HL60-Diff-R). These data support the development of strategies to stimulate autophagy as a novel approach to promote differentiation in AML.
急性髓系白血病（AML）的特征是骨髓中未成熟血细胞前体的积累。从药理学角度克服这种情况下的分化阻滞是一条有吸引力的治疗途径，但仅在AML的一个亚型——急性早幼粒细胞白血病（APL）中取得了成功。迄今为止，在其他AML亚型中模仿这一成功的尝试均未成功。自噬是一种保守的蛋白质降解途径，在哺乳动物细胞分化中，尤其是在造血系统中发挥重要作用。在本文所述的研究中，我们研究了自噬在APL细胞分化中的功能重要性。我们发现，在全反式维甲酸（ATRA）诱导APL细胞系NB4向粒细胞分化的过程中，自噬增强，且这与参与自噬体形成的LC3II和GATE-16蛋白表达增加有关。使用药物（氯喹/3-甲基腺嘌呤）或靶向必需自噬基因ATG7的短发夹RNA抑制自噬，会减弱髓系分化。重要的是，我们发现增强自噬可促进非APL AML HL60细胞系（HL60-Diff-R）的ATRA抗性衍生物的ATRA诱导的粒细胞分化。这些数据支持开发刺激自噬的策略，作为促进AML分化的一种新方法。
