Transcription-coupled genetic instability marks acute lymphoblastic leukemia structural variation hotspots

Area of Science:

• Genetics
• Molecular Biology
• Oncology

Background:

• Malignancy progression involves genetic alterations.
• Activation-induced deaminase (AID) can cause DNA breaks, driving lymphomagenesis.
• Convergent transcription and enhancer activity are implicated in off-target DNA breaks.

Purpose of the Study:

• To investigate transcriptional features at structural variation (SV) sites in acute lymphoblastic leukemia (ALL).
• To identify vulnerable genomic regions prone to DNA breaks.
• To quantify the role of convergent transcription in R-loop generation and RNA polymerase stalling.

Main Methods:

• Analysis of active transcriptional profiles from ALL patients.
• Signal feature analysis to detect vulnerable genomic regions.
• Quantification of R-loop generation and RNA polymerase stalling in human cells.

Main Results:

• Convergent transcription and Pol2 stalling were identified at SV breakpoints in ALL.
• These features were prominent at SVs with recombination-activating genes (RAG) motifs.
• High DNAse hypersensitivity and H3K4me3 signals characterized wide stalling regions.
• ETV6-RUNX1 positive pre-B-ALL showed elevated RAG1; high AID expression marked pre-B-ALL lacking common cytogenetic changes.

Conclusions:

• Convergent transcription contributes to R-loop formation and RNA polymerase stalling at vulnerable DNA sites.
• Specific transcriptional vulnerabilities are associated with distinct genetic profiles in pre-B-ALL.
• Understanding these mechanisms may offer new therapeutic targets for leukemia.