Research has unveiled significant molecular and pharmacological heterogeneity among children with ETV6::RUNX1 acute lymphoblastic leukemia (ALL), leading to two distinct subtypes with varying clinical characteristics and treatment responses. This groundbreaking study, published on January 30, 2025, by researchers at St. Jude Children’s Research Hospital, analyzed the genomic profiles and drug sensitivities of 194 pediatric patients to differentiate between these subtypes.
ETV6::RUNX1 is recognized as the most common gene fusion found in childhood ALL, accounting for 20%-30% of cases. Generally associated with favorable outcomes, this subtype nonetheless presents treatment challenges due to relapse rates and the potential for overtreatment. This recent research aims to clarify the underlying biological mechanisms of the disease to fine-tune treatment protocols.
The researchers employed whole transcriptome and genome sequencing alongside hormone drug sensitivity testing, identifying two transcriptomic clusters labeled C1 and C2. The C1 subtype, comprising 61% of patients, features poorer early treatment responses and higher drug resistance compared to the C2 subtype, which includes 39% of patients and shows greater sensitivity to therapies involving thiopurines and prednisolone.
Dr. Z. Li, one of the lead researchers, emphasizes how these findings point to the necessity of considering molecular heterogeneity when designing treatments for ETV6::RUNX1 ALL. "Our results point to molecular heterogeneity within ETV6::RUNX1 ALL linked to divergent drug responses," noted Li.
C2 patients were identified to often present with higher white blood cell counts and are typically diagnosed at younger ages than those classified as C1. Interestingly, the presence of certain genomic deletions, particularly impacting the PAX5 gene, appears to play a key role in these differences. The study found significant enrichment of PAX5 deletions within the C2 subtype, affecting therapeutic outcomes.
Despite the notable sensitivity of the C2 subtype to treatment, the characteristics of these patients could result in them receiving overly aggressive therapy regimes based on current risk stratification methods. This study's insights suggest potential avenues for de-intensifying treatment for C2 patients, as their positive responses to shorter courses of therapy could lead to successful cures.
Further analysis revealed exploratory pathways involved and differential gene expressions unique to each subtype. These findings not only contribute to the broader scientific comprehension of ETV6::RUNX1 ALL but also underline the intricacies of leukemic transformations and responses to chemotherapy.
This research highlights the importance of using genomic data to refine and potentially personalize treatment strategies for younger patients battling this common leukemia subtype. Researchers believe the detailed characteristics of ETV6::RUNX1 subtypes can aid clinicians in making informed decisions about treatment intensity, tailoring it to individuals' unique molecular profiles.
"C2 is more sensitive to thiopurines and prednisolone, partially explained by the enrichment of PAX5 deletions," explained the authors of the article, showcasing the potential for more individualized approaches to treatment moving forward.
Overall, the study sets the stage for future clinical exploration centered on personalized therapies aimed at maximizing the efficacy of treatments for pediatric ETV6::RUNX1 ALL, ensuring children receive the most appropriate care based on the molecular characteristics of their leukemia. "These findings may guide more personalized treatment approaches for patients with this common pediatric ALL subtype," the authors added.