Disrupting a Convergent Acetylation Circuit Collapses Leukemic Identity Across AML Subtypes

Area of Science:

• Molecular Biology
• Gene Regulation
• Cancer Biology

Background:

• Transcriptional condensates regulate gene expression but their assembly is poorly understood.
• The Super Elongation Complex (SEC) is crucial for transcriptional elongation.
• Regulation of SEC integrity is vital for understanding gene expression control.

Purpose of the Study:

• To identify regulatory mechanisms governing transcriptional condensate integrity.
• To investigate the role of acetylation in SEC function.
• To explore KAT2A/B degradation as a therapeutic strategy for acute myeloid leukemia (AML).

Main Methods:

• Utilized a PROTAC (GSK983/GSK699) to degrade KAT2A/KAT2B.
• Assessed histone H3 lysine 9 acetylation (H3K9ac) and SEC component acetylation.
• Analyzed displacement of the chromatin reader ENL and dissolution of transcriptional condensates.
• Employed genome-scale dependency data to evaluate SAGA complex dependency in AML.

Main Results:

• Identified an acetylation-dependent feed-forward circuit controlling SEC integrity.
• KAT2A/KAT2B license dual acetylation of H3K9ac and SEC components (ENL, AFF1, AFF3).
• KAT2A/B degradation displaced ENL, dissolved condensates, and disrupted SEC-dependent transcription.
• SAGA complex is a selective dependency in AML; KAT2A/B degradation showed pan-AML anti-leukemic activity.

Conclusions:

• KAT2A/B degradation dismantles ENL-anchored condensates and depletes H3K9ac at AML oncogene loci.
• KAT2A/B licenses SEC acetylation and ENL interaction, crucial for transcriptional regulation.
• The SAGA complex is essential in hematological malignancies, particularly AML.
• KAT2A/B degradation represents a mechanism-based, pan-AML therapeutic strategy.