Effect of endoplasmic reticulum stress induced by all-trans retinoic acid on apoptosis of FLT3-ITD mutated leukemia cells by activating autophagy in FLT3-ITD mutated protein
10.3760/cma.j.issn.0253-2727.2020.10.008
- VernacularTitle:全反式维甲酸调控内质网应激诱导FLT3-ITD蛋白自噬降解促进白血病细胞凋亡
- Author:
Limin ZHENG
1
;
Li’na WANG
;
Cong LIANG
;
Chunjin PENG
;
Wenyan TANG
;
Xiaoli ZHANG
;
Yu LI
;
Yanlai TANG
;
Libin HUANG
;
Xuequn LUO
Author Information
1. 中山大学附属第一医院儿科，广州 510000
- Keywords:
Leukemia, myeloid, acute;
FLT3-ITD protein;
All-trans retinoic acid;
Endoplasmic reticulum stress
- From:
Chinese Journal of Hematology
2020;41(10):836-842
- CountryChina
- Language:Chinese
-
Abstract:
Objective:Endoplasmic reticulum stress(ERS)was used as the research emphasis to further investigate the mechanisms of apoptosis of FLT3-ITD-mutated leukemia cells and decreased expression of FLT3-ITD mutated protein induced by all-trans retinoic acid(ATRA).Methods:FLT3-ITD-mutated leukemia cell lines(MV4-11 and MOLM13)were treated with ATRA. Flow cytometry was conducted to assess cell apoptosis. Real-time fluorescent quantitative PCR(RT-qPCR)and Western blot were used to detect the expression of ERS-related and autophagy-related genes and protein, respectively.Results:A low-dose ATRA further increased FLT3-ITD cells and ERS levels. ATRA acted on the ERS-related PERK/eif2ɑ signaling pathway and continued to increase the ERS of FLT3-ITD cells, resulting in an upregulation of apoptotic gene CHOP expression. After the treatment with ATRA, FLT3-ITD protein in FLT3-ITD cells was decreased. Of the two main ERS-related protein degradation pathways, ER-associated degradation(ERAD)and ER-activated autophagy(ERAA), the expression of ERAD-related protein ATF6 in FLT3-ITD cells was not significantly changed on ATRA, whereas the expression of ERAA-related proteins Atg7 and Atg5 were significantly increased.Conclusions:ATRA further raises the ERS level of FLT3-ITD cells continuously by activating the ERS-related PERK/eif2ɑ signal pathway and induces FLT3-ITD protein autophagy degradation through ERAA pathway, which induces apoptosis of FLT3-ITD-mutated leukemia cells. These results provide preliminary evidence on the use of ATRA in the treatment of refractory leukemia with FLT3-ITD.
