AI Insight
This study examined whether off-target activity of recombination-activating genes (RAG), which generate structural variants (SVs) in the genome, can predict relapse risk in pediatric B-cell acute lymphoblastic leukemia (B-ALL). Analyzing sequencing data from 1,496 pediatric patients, researchers found that RAG-mediated SVs bearing a recombination signal sequence at a breakpoint were significantly more common at diagnosis in patients who later relapsed, with each additional SV increasing the odds of relapse by approximately 8 percent. This association held across molecular subtypes and remained significant even in patients who tested negative for minimal residual disease, a standard clinical marker of treatment response.
Why it matters
These findings suggest that RAG-mediated SV burden could serve as a complementary biomarker at diagnosis to better stratify relapse risk in pediatric ALL patients, potentially allowing for earlier or more targeted therapeutic interventions, including in patients who appear to be responding well to treatment by conventional measures.
⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Relapse during treatment of B-cell acute lymphoblastic leukemia (B-ALL) is a harbinger of poor outcomes. Identifying biomarkers for subsequent relapse risk which are detectable at B-ALL diagnosis remains a priority. Off-target recombination-activating gene (RAG)-mediated structural variants (SVs) generate genomic instability that drives leukemogenesis and may underlie treatment resistance. Leveraging sequencing data in 1,496 pediatric B-ALL patients enriched for relapse status (relapse n=532; non-relapse n=964), we characterized RAG-mediated SVs across B-ALL molecular subtypes and examined their association with patient characteristics and their impact on clinical outcomes. Off-target RAG-mediated SVs were overall frequent, particularly in ETV6::RUNX1, ETV6::RUNX1-like, and Ph-like B-ALL subtypes, while increasing age-at-diagnosis was positively associated with burden of off-target RAG-mediated SVs (P<.001). Off-target RAG-mediated SVs with a recombination signal sequence (RSS) at one breakpoint, a hallmark of off-target RAG activity, were significantly more frequent at diagnosis in patients who subsequently relapsed (P=.001). This association remained significant in multivariable regression analysis (per SV odds ratio [OR]:1.08, 95%CI:1.04-1.12), in minimal residual disease (MRD)-negative patients (OR:1.09, 95%CI:1.04-1.14) and across subtypes. Excluding deletions, MRD-negative ETV6::RUNX1 patients with 3 off-target RAG-mediated SVs had a >3-fold risk of relapse (hazard ratio:3.47, 95%CI:1.86- 6.49). RAG-mediated SVs were also associated with relapse risk in T-cell ALL patients. Off-target RAG-mediated SV burden at diagnosis is a risk factor of relapse in pediatric ALL across molecular subtypes and independent of MRD status.
Source: RAG-mediated structural variation and its impact on relapse risk in acute lymphoblastic leukemia