m6A Modification of ATOX1 Inhibits Acute Myeloid Leukemia Progression by Promoting Cuproptosis

Area of Science:

• Cellular Biology
• Oncology
• Biochemistry

Background:

• Cuproptosis is a regulated cell death pathway linked to proteotoxic stress, involving copper-dependent enzymes in the TCA cycle.
• The copper chaperone ATOX1 is implicated in cuproptosis, but its role in acute myeloid leukemia (AML) progression is not well understood.

Purpose of the Study:

• To investigate the role of ATOX1 in AML progression and its regulation by ALKBH5-mediated m6A modification.
• To explore the potential of targeting the ALKBH5-ATOX1 axis for AML treatment.

Main Methods:

• Induction and inhibition of cuproptosis using elesclomol (ES), disulfiram (DSF)/Cu, and bathocuproine disulfonic acid (BCS).
• Assessment of cell viability, proliferation, cell cycle, and cell death in AML cells with altered ATOX1 expression.
• Establishment of an AML xenograft mouse model to validate findings in vivo.
• Investigation of m6A modification of ATOX1 mediated by ALKBH5.

Main Results:

• ATOX1 expression is downregulated in AML, and its knockdown promotes AML cell viability and proliferation while reducing cell death.
• ATOX1 overexpression enhances cuproptosis in AML cells, an effect counteracted by BCS.
• ALKBH5 mediates m6A modification of ATOX1, thereby regulating its expression and influencing cuproptosis in AML.
• The ALKBH5-ATOX1 axis plays a significant role in AML progression in vivo.

Conclusions:

• The demethylase ALKBH5 downregulates ATOX1 by reducing its m6A levels, which modulates cuproptosis in AML.
• The ALKBH5-ATOX1 axis represents a potential novel therapeutic target for AML treatment.