JUN mediates glucocorticoid resistance by stabilizing HIF1a in T cell acute lymphoblastic leukemia

Zhijie Zhang; Jiangzhou Shi; Qifang Wu; Zijian Zhang; Xiaoyan Liu; Anqi Ren; Guanlin Zhao; Ge Dong; Han Wu; Jiaxuan Zhao; Yuan Zhao; Jia Hu; Hui Li; Tongcun Zhang; Fuling Zhou; Haichuan Zhu

doi:10.1016/j.isci.2023.108242

JUN mediates glucocorticoid resistance by stabilizing HIF1a in T cell acute lymphoblastic leukemia

iScience. 2023 Oct 18;26(11):108242. doi: 10.1016/j.isci.2023.108242. eCollection 2023 Nov 17.

Authors

Zhijie Zhang¹, Jiangzhou Shi¹, Qifang Wu¹, Zijian Zhang¹, Xiaoyan Liu², Anqi Ren¹, Guanlin Zhao¹, Ge Dong¹, Han Wu¹, Jiaxuan Zhao³, Yuan Zhao¹, Jia Hu¹, Hui Li⁴, Tongcun Zhang^{1

3}, Fuling Zhou², Haichuan Zhu¹

Affiliations

¹ Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Wuhan 430081, China.
² Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
³ Key Lab of Industrial Fermentation Microbiology of the Ministry of Education & Tianjin Key Lab of Industrial Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China.
⁴ Tianyou Hospital affiliated to Wuhan University of Science and Technology, Wuhan 430064, China.

Abstract

Dexamethasone (Dex) plays a critical role in T-ALL treatment, but the mechanisms of Dex resistance are poorly understood. Here, we demonstrated that the expression of JUN was regulated in Dex-resistant T-ALL cell lines and patient samples. JUN knockdown increased the sensitivity to Dex. Moreover, the survival data showed that high expression of JUN related to poor prognosis of T-ALL patients. Then, we generated dexamethasone-resistant clones and conducted RNA-seq and ATAC-seq. We demonstrated that the upregulation of JUN was most significant and regulated by JNK pathway in Dex-resistant cells. High-throughput screening showed that HIF1α inhibitors synergized with Dex could enhance Dex resistance cells death in vitro and in vivo. Additionally, JUN combined and stabilized HIF1α in Dex resistance cells. These results reveal a new mechanism of Dex resistance in T-ALL and provide experimental evidence for the potential therapeutic benefit of targeting the JNK-JUN-HIF1α axis for T-ALL treatment.

Keywords: Biological sciences; Cancer; Natural sciences; Pharmacology; Physiology; Systems biology.