Convergent epigenetic evolution drives relapse in acute myeloid leukemia

Area of Science:

• Hematology
• Cancer Biology
• Epigenetics

Background:

• Relapse of acute myeloid leukemia (AML) is aggressive and treatment-refractory.
• Approximately 40% of AML relapses lack driver mutation changes, suggesting non-genetic mechanisms.
• Understanding relapse mechanisms is crucial for improving patient outcomes.

Purpose of the Study:

• To investigate epigenetic patterns driving AML relapse.
• To determine if epigenetic changes occur independently of mutational alterations.
• To characterize epigenetic evolution in leukemia stem cells (LSCs) and non-LSCs during relapse.

Main Methods:

• Analysis of 26 matched diagnosis-relapse AML samples using ATAC-seq.
• Chromatin accessibility profiling to identify relapse-specific epigenetic signatures.
• Single-cell ATAC-seq (scATAC) combined with mitochondrial sequencing (mtscATAC) to track clonal evolution and epigenetic features.

Main Results:

• Identified a relapse-specific chromatin accessibility signature in mutationally stable AML.
• Demonstrated that AML undergoes epigenetic evolution at relapse, independent of genetic mutations.
• Found that LSCs exhibit less epigenetic evolution than non-LSCs at relapse.
• Observed convergent epigenetic evolution, where distinct clones show similar chromatin accessibility at relapse.

Conclusions:

• Epigenetic evolution is a significant feature of relapsed AML.
• Convergent epigenetic evolution can occur in relapsed AML following chemotherapy.
• Non-genetic mechanisms, particularly epigenetic alterations, play a critical role in AML relapse.