A synergistic interaction between PRMT5 and LSD1 inhibitors in AML

Area of Science:

• Hematology
• Oncology
• Molecular Biology

Background:

• Acute myeloid leukemia (AML) is a cancer of blood-forming tissues.
• PRMT5 is implicated in AML stem cell maintenance and is a potential therapeutic target.
• Complete PRMT5 inhibition causes toxicity, necessitating synergistic therapies.

Purpose of the Study:

• To identify synergistic therapies for AML by targeting PRMT5-regulated pathways.
• To investigate the synthetic lethal interaction between PRMT5 and LSD1 inhibition in AML.

Main Methods:

• Conducted a targeted screen of compounds inhibiting PRMT5-regulated pathways.
• Identified synthetic lethality between PRMT5 and LSD1 inhibition.
• Generated dual compounds targeting both PRMT5 and LSD1.
• Analyzed transcriptome changes and p53 dependency.

Main Results:

• A synthetic lethal interaction was found between PRMT5 and LSD1 inhibition in AML.
• Combined inhibition reshaped the transcriptome, promoting AML differentiation.
• Synergistic effects included growth inhibition and apoptosis, dependent on p53.
• Dual compounds recapitulated the combination therapy effects.

Conclusions:

• The study uncovers a convergence of PRMT5 and LSD1 targets in AML.
• This synthetic lethal interaction provides a basis for novel AML therapeutic strategies.
• Targeting both PRMT5 and LSD1 offers a promising avenue for AML treatment.