The Clinical Relevance of RAS Pathway Gene Mutations in Pediatric B-Cell Acute Lymphoblastic Leukemia

Objective High-throughput sequencing has elucidated the genetic landscape of B-cell acute lymphoblastic leukemia (B-ALL). Notably, FLT3 and RAS pathway gene mutations represent a significant proportion of pediatric cases. Our study explores whether these patients have distinct clinical features and prognostic outcomes. Methods We retrospectively analyzed 562 pediatric B-ALL cases from the CCCG-ALL-2015 cohort using whole transcriptome sequencing to assess the clinical features of FLT3 mutations, RAS pathway alterations ( NRAS, KRAS, PTPN11, NF1 ), and their cooperative effects. Results Among the cohort, 224 patients (39.86%) carried at least one RAS pathway alterations ( NRAS , n = 120; KRAS , n = 109; PTPN11 , n = 57; NF1 , n = 11), while 82 patients (14.59%) had FLT3 mutations. Strikingly, 6 of 11 NF1 -mutated patients harbored concurrent FLT3 mutations. A significant correlation was observed between FLT3 and NF1 mutations (Phi coefficient = 0.16, χ² = 11.518, p  < 0.0001), NRAS and KRAS mutations (Phi coefficient = 0.17, χ² = 15.713, p  < 0.0001). Patients with FLT3/NF1 co-mutations exhibited a higher frequency of abnormal karyotypes. Survival analysis revealed that these patients had significantly poorer overall survival (OS) and event-free survival (EFS) ( p  < 0.05), particularly when compared to those without KMT2A rearrangements ( p  = 0.0022 and p  = 0.0026, respectively). Collectively, RAS pathway alterations were not significantly associated with inferior OS or EFS. Multivariate Cox regression analysis confirmed that FLT3/NF1 co-mutations, as a distinct molecular subtype, were independently associated with inferior OS (HR: 18.663, 95% CI: 2.203–158.106; p  = 0.007) and EFS (HR: 4.986, 95% CI: 1.167–21.304; p  = 0.03). PTPN11 mutations (HR 2.67, 95% CI 1.41–5.04) and FLT3/NF1 co-mutations (HR 7.08, 95% CI 1.22–41.09) also showed significant associations with Day 19 MRD ≥ 0.1% and Day 46 MRD ≥ 0.01%, respectively. Conclusion Our findings demonstrate that FLT3/NF1 co-mutations, but not RAS pathway mutations, defined high-risk pediatric B-ALL with poor outcomes. Trial registration : The study was conducted with approval from the Institutional Review Board of Children's Hospital of Soochow University (Approval number: 2019KS006).