Subtype-specific 3D genome alteration in acute myeloid leukaemia

Area of Science:

• Genomics
• Cancer Biology
• Epigenetics

Background:

• Acute myeloid leukaemia (AML) is a complex blood cancer characterized by genetic mutations.
• The role of 3D genome structure alterations in AML pathogenesis remains largely unknown.

Purpose of the Study:

• To investigate the impact of AML-associated mutations on the 3D chromatin architecture.
• To identify novel regulatory elements and loops contributing to AML development and progression.

Main Methods:

• Hi-C and whole-genome sequencing on AML patient samples and healthy donors.
• RNA sequencing, ATAC-seq, and CUT&Tag for epigenetic marks (CTCF, H3K27ac, H3K27me3).
• CRISPR-based functional validation and whole-genome bisulfite sequencing.

Main Results:

• Identified recurrent and subtype-specific alterations in A/B compartments, TADs, and chromatin loops in AML.
• Discovered AML-specific promoter-enhancer and promoter-silencer loops, with validated roles in gene regulation.
• Revealed structural variation-induced enhancer-hijacking and silencer-hijacking events impacting AML cell growth and gene expression.

Conclusions:

• 3D genome alterations are significant drivers in acute myeloid leukaemia.
• Repressive loops and hijacked cis-regulatory elements represent potential therapeutic targets in AML.
• DNA methylation, CTCF binding, and 3D genome structure are intricately linked and manipulable in AML.