Targeting IFN-γ-inducible lysosomal thiol reductase overcomes chemoresistance in AML through regulating the ROS-mediated mitochondrial damage

Li-Ting Niu; Yu-Qing Wang; Catherine C L Wong; Shuai-Xin Gao; Xiao-Dong Mo; Xiao-Jun Huang

doi:10.1016/j.tranon.2021.101159

Targeting IFN-γ-inducible lysosomal thiol reductase overcomes chemoresistance in AML through regulating the ROS-mediated mitochondrial damage

Transl Oncol. 2021 Sep;14(9):101159. doi: 10.1016/j.tranon.2021.101159. Epub 2021 Jul 9.

Authors

Li-Ting Niu¹, Yu-Qing Wang², Catherine C L Wong³, Shuai-Xin Gao⁴, Xiao-Dong Mo¹, Xiao-Jun Huang⁵

Affiliations

¹ 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.
² 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.
³ 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.
⁴ Center for Precision Medicine Multi-Omics Research, Peking University Health Science Center, Peking University, Beijing 100191, China.
⁵ 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.

Abstract

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-γ-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.

Keywords: AML; Chemoresistance; GILT; LSC; Oxidative stress.