Targeting enhancer switching overcomes non-genetic drug resistance in acute myeloid leukaemia

Area of Science:

• Oncology
• Molecular Biology
• Epigenetics

Background:

• Non-genetic drug resistance is a significant challenge in cancer therapy, particularly in acute myeloid leukemia (AML).
• The molecular mechanisms underlying stable non-genetic resistance remain poorly understood.
• Effective strategies to overcome this resistance are urgently needed.

Purpose of the Study:

• To elucidate the molecular drivers of stable non-genetic drug resistance in AML.
• To identify therapeutic targets capable of overcoming established epigenetic resistance.
• To investigate the role of transcriptional plasticity and enhancer regulation in drug resistance.

Main Methods:

• Single-cell RNA sequencing of paired drug-naïve and resistant AML patient samples.
• Cellular barcoding in a novel mouse model of non-genetic resistance.
• CRISPR-Cas9 screening to identify regulators of enhancer function.

Main Results:

• Transcriptional plasticity drives stable epigenetic resistance in AML.
• Regulators of enhancer function are critical modulators of the resistant cell state.
• Lsd1 (Kdm1a) inhibition overcomes stable epigenetic resistance by facilitating pioneer factor binding (Pu.1, Irf8) to nucleate new enhancers.
• This enhancer switching leads to the redistribution of transcriptional co-activators like Brd4, enabling therapeutic intervention.

Conclusions:

• Stable non-genetic drug resistance is epigenetically driven and characterized by transcriptional plasticity.
• Targeting Lsd1 (Kdm1a) offers a promising strategy to overcome epigenetic resistance in AML.
• Understanding enhancer dynamics and co-activator redistribution is key to developing novel therapeutic approaches against drug-resistant cancers.