ABSTRACT

Although molecular targeted therapies have recently displayed therapeutic effects in acute myeloid leukemia (AML), limited response and acquired resistance remain common problems. Numerous studies have associated autophagy, an essential degradation process involved in the cellular response to stress, with the development and therapeutic response of cancers including AML. Thus, we review studies on the role of autophagy in AML development and summarize the linkage between autophagy and several recurrent genetic abnormalities in AML, highlighting the potential of capitalizing on autophagy modulation in targeted therapy for AML.

Abbreviations: AML: acute myeloid leukemia; AMPK: AMP-activated protein kinase; APL: acute promyelocytic leukemia; ATG: autophagy related; ATM: ATM serine/threonine kinase; ATO: arsenic trioxide; ATRA: all trans retinoic acid; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; BET proteins, bromodomain and extra-terminal domain family; CMA: chaperone-mediated autophagy; CQ: chloroquine; DNMT, DNA methyltransferase; DOT1L: DOT1 like histone lysine methyltransferase; FLT3: fms related receptor tyrosine kinase 3; FIS1: fission, mitochondrial 1; HCQ: hydroxychloroquine; HSC: hematopoietic stem cell; IDH: isocitrate dehydrogenase; ITD: internal tandem duplication; KMT2A/MLL: lysine methyltransferase 2A; LSC: leukemia stem cell; MDS: myelodysplastic syndromes; MTORC1: mechanistic target of rapamycin kinase complex 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NPM1: nucleophosmin 1; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PML: PML nuclear body scaffold; ROS: reactive oxygen species; RB1CC1/FIP200: RB1 inducible coiled-coil 1; SAHA: vorinostat; SQSTM1: sequestosome 1; TET2: tet methylcytosine dioxygenase 2; TKD: tyrosine kinase domain; TKI: tyrosine kinase inhibitor; TP53/p53: tumor protein p53; ULK1: unc-51 like autophagy activating kinase 1; VPA: valproic acid; WDFY3/ALFY: WD repeat and FYVE domain containing 3.

摘要

尽管分子靶向疗法最近在急性髓性白血病 (AML) 中显示出治疗效果，但反应有限和获得性耐药仍然是常见问题。许多研究已将自噬（一种参与细胞对压力反应的重要降解过程）与包括 AML 在内的癌症的发展和治疗反应联系起来。因此，我们回顾了关于自噬在 AML 发展中的作用的研究，并总结了自噬与 AML 中几种复发性遗传异常之间的联系，强调了在 AML 靶向治疗中利用自噬调节的潜力。

缩写: AML：急性髓性白血病；AMPK：AMP激活的蛋白激酶；APL：急性早幼粒细胞白血病；ATG：自噬相关；ATM：ATM丝氨酸/苏氨酸激酶；ATO：三氧化二砷；ATRA：全反式维甲酸；BCL2：BCL2 凋亡调节剂；BECN1：beclin 1；BET 蛋白、溴结构域和末端外结构域家族；CMA：伴侣介导的自噬；CQ：氯喹；DNMT，DNA甲基转移酶；DOT1L：DOT1 样组蛋白赖氨酸甲基转移酶；FLT3：fms相关受体酪氨酸激酶3；FIS1：裂变，线粒体1；HCQ：羟氯喹；HSC：造血干细胞；IDH：异柠檬酸脱氢酶；ITD：内部串联复制；KMT2A/MLL：赖氨酸甲基转移酶 2A；LSC：白血病干细胞；MDS：骨髓增生异常综合征；MTORC1：雷帕霉素激酶复合物 1 的机械靶点；MAP1LC3/LC3：微管相关蛋白 1 轻链 3；NPM1：核磷蛋白 1；PIK3C3/VPS34：磷脂酰肌醇 3-激酶催化亚基 3 型；PML：PML核体支架；ROS：活性氧；RB1CC1/FIP200：RB1 感应线圈1；SAHA：伏立诺他；SQSTM1：隔离体 1；TET2：tet甲基胞嘧啶双加氧酶2；TKD：酪氨酸激酶结构域；TKI：酪氨酸激酶抑制剂；TP53/p53：肿瘤蛋白p53；ULK1：unc-51 样自噬激活激酶 1；VPA：丙戊酸；WDFY3/ALFY：包含 3 个的 WD 重复和 FYVE 结构域。TKI：酪氨酸激酶抑制剂；TP53/p53：肿瘤蛋白p53；ULK1：unc-51 样自噬激活激酶 1；VPA：丙戊酸；WDFY3/ALFY：包含 3 个的 WD 重复和 FYVE 结构域。TKI：酪氨酸激酶抑制剂；TP53/p53：肿瘤蛋白p53；ULK1：unc-51 样自噬激活激酶 1；VPA：丙戊酸；WDFY3/ALFY：包含 3 个的 WD 重复和 FYVE 结构域。