Journal
ISCIENCE
Volume 26, Issue 11, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.isci.2023.108242
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A new study reveals that high expression of JUN is associated with poor prognosis in T-ALL patients, and targeting the JNK-JUN-HIF1 alpha axis can enhance the death of Dex-resistant cells, providing a potential therapeutic strategy for T-ALL treatment.
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 HIF1 alpha inhibitors synergized with Dex could enhance Dex resistance cells death in vitro and in vivo. Additionally, JUN combined and stabilized HIF1a 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-HIF1 alpha axis for T-ALL treatment.
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