PMID- 34252711
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210807
IS  - 1936-5233 (Print)
IS  - 1936-5233 (Electronic)
IS  - 1936-5233 (Linking)
VI  - 14
IP  - 9
DP  - 2021 Sep
TI  - Targeting IFN-gamma-inducible lysosomal thiol reductase overcomes chemoresistance in 
      AML through regulating the ROS-mediated mitochondrial damage.
PG  - 101159
LID - S1936-5233(21)00151-0 [pii]
LID - 10.1016/j.tranon.2021.101159 [doi]
LID - 101159
AB  - The persistence of leukemia stem cells (LSCs) is one of the leading causes of 
      chemoresistance in acute myeloid leukemia (AML). To explore the factors important 
      in LSC-mediated resistance, we use mass spectrometry to screen the factors 
      related to LSC chemoresistance and defined IFN-gamma-inducible lysosomal thiol 
      reductase (GILT) as a candidate. We found that the GILT expression was 
      upregulated in chemoresistant CD34+ AML cells. Loss of function studies 
      demonstrated that silencing of GILT in AML cells sensitized them to Ara-C 
      treatment both in vitro and in vivo. Further mechanistic findings revealed that 
      the ROS-mediated mitochondrial damage plays a pivotal role in inducing apoptosis 
      of GILT-inhibited AML cells after Ara-C treatment. The inactivation of PI3K/Akt/ 
      nuclear factor erythroid 2-related factor 2 (NRF2) pathway, causing reduced 
      generation of antioxidants such as SOD2 and leading to a shifted ratio of 
      GSH/GSSG to the oxidized form, contributed to the over-physiological oxidative 
      status in the absence of GILT. The prognostic value of GILT was also validated in 
      AML patients. Taken together, our work demonstrated that the inhibition of GILT 
      increases AML chemo-sensitivity through elevating ROS level and induce oxidative 
      mitochondrial damage-mediated apoptosis, and inhibition of the PI3K/Akt/NRF2 
      pathway enhances the intracellular oxidative state by disrupting redox 
      homeostasis, providing a potentially effective way to overcome chemoresistance of 
      AML.
CI  - Copyright (c) 2021. Published by Elsevier Inc.
FAU - Niu, Li-Ting
AU  - Niu LT
AD  - Peking University People's Hospital, Peking University Institute of Hematology, 
      National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory 
      of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China.
FAU - Wang, Yu-Qing
AU  - Wang YQ
AD  - Peking University People's Hospital, Peking University Institute of Hematology, 
      National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory 
      of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China; 
      Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871.
FAU - Wong, Catherine C L
AU  - Wong CCL
AD  - Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871,; 
      Center for Precision Medicine Multi-Omics Research, Peking University Health 
      Science Center, Peking University, Beijing 100191, China.; School of Basic 
      Medical Sciences, Peking University Health Science Center, Beijing 100191, China; 
      Peking University First Hospital, Beijing, 100034, China.
FAU - Gao, Shuai-Xin
AU  - Gao SX
AD  - Center for Precision Medicine Multi-Omics Research, Peking University Health 
      Science Center, Peking University, Beijing 100191, China.
FAU - Mo, Xiao-Dong
AU  - Mo XD
AD  - Peking University People's Hospital, Peking University Institute of Hematology, 
      National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory 
      of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China.
FAU - Huang, Xiao-Jun
AU  - Huang XJ
AD  - Peking University People's Hospital, Peking University Institute of Hematology, 
      National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory 
      of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China; 
      Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871,. 
      Electronic address: huangxiaojun@bjmu.edu.cn.
LA  - eng
PT  - Journal Article
DEP - 20210709
PL  - United States
TA  - Transl Oncol
JT  - Translational oncology
JID - 101472619
PMC - PMC8319687
OTO - NOTNLM
OT  - AML
OT  - Chemoresistance
OT  - GILT
OT  - LSC
OT  - Oxidative stress
COIS- The authors have declared no conflicts of interest.
EDAT- 2021/07/13 06:00
MHDA- 2021/07/13 06:01
PMCR- 2021/07/09
CRDT- 2021/07/12 20:23
PHST- 2021/06/13 00:00 [received]
PHST- 2021/06/14 00:00 [accepted]
PHST- 2021/07/13 06:00 [pubmed]
PHST- 2021/07/13 06:01 [medline]
PHST- 2021/07/12 20:23 [entrez]
PHST- 2021/07/09 00:00 [pmc-release]
AID - S1936-5233(21)00151-0 [pii]
AID - 101159 [pii]
AID - 10.1016/j.tranon.2021.101159 [doi]
PST - ppublish
SO  - Transl Oncol. 2021 Sep;14(9):101159. doi: 10.1016/j.tranon.2021.101159. Epub 2021 
      Jul 9.