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

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Dexamethasone (Dex) is crucial for treating T-cell acute lymphoblastic leukemia (T-ALL).
• Mechanisms underlying Dex resistance in T-ALL remain largely unknown.
• Understanding resistance pathways is vital for improving patient prognosis.

Purpose of the Study:

• Investigate the role of JUN in Dex resistance in T-ALL.
• Elucidate the molecular mechanisms connecting JUN, JNK, and HIF1α in Dex-resistant T-ALL.
• Identify potential therapeutic strategies targeting the JNK-JUN-HIF1α axis.

Main Methods:

• Analysis of JUN expression in Dex-resistant T-ALL cell lines and patient samples.
• JUN knockdown experiments to assess Dex sensitivity.
• RNA-sequencing (RNA-seq) and ATAC-sequencing (ATAC-seq) on Dex-resistant clones.
• High-throughput screening for synergistic drug combinations.
• In vitro and in vivo validation of therapeutic targets.

Main Results:

• JUN expression was upregulated in Dex-resistant T-ALL and associated with poor prognosis.
• JUN knockdown resensitized T-ALL cells to Dex.
• The JNK pathway significantly regulated JUN upregulation in Dex-resistant cells.
• JUN physically interacted with and stabilized Hypoxia-Inducible Factor 1-alpha (HIF1α).
• HIF1α inhibitors synergized with Dex to induce cell death in vitro and in vivo.

Conclusions:

• A novel mechanism of Dex resistance in T-ALL involving the JNK-JUN-HIF1α axis was identified.
• JUN acts as a key mediator in Dex resistance by stabilizing HIF1α.
• Targeting the JNK-JUN-HIF1α pathway presents a promising therapeutic strategy for overcoming Dex resistance in T-ALL.