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<p>Objective: Notably, FLT3 and RAS pathway gene mutations represent a significant proportion of childhood B-cell acute lymphoblastic leukemia (B-ALL) cases. Our study explores whether these patients have distinct clinical features and prognostic outcomes. Methods: We retrospectively analyzed 488 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, and their cooperative effects. Results: 192 patients (39.3%) carried at least one RAS pathway alterations, while 76 patients (15.6%) 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 = 13.0, p &lt; 0.001), NRAS and KRAS mutations (Phi coefficient = 0.19, χ² = 17.12, p &lt; 0.0001), NRAS and PTPN11 (Phi coefficient = 0.138, χ² = 9.54, p = 0.0042). FLT3/NF1 co-mutated patients exhibited a higher frequency of abnormal karyotypes and had significantly poorer overall survival (OS) and event-free survival (EFS) (p &lt; 0.05), particularly when compared to those without KMT2A rearrangements (p = 0.004 and p = 0.003, respectively). Collectively, RAS pathway alterations were not significantly associated with inferior OS or EFS. Multivariable Cox regression analysis confirmed that FLT3/NF1 co‑mutations were independently associated with inferior OS (HR = 12.39, 95% CI: 1.40-109.46, p = 0.024), and multivariable logistic regression analysis showed that they were also independently associated with Day 46 MRD ≥ 0.01% (OR = 9.50, 95% CI: 1.65–54.71, p = 0.01). Conclusion: Our findings suggest that FLT3/NF1 co-mutations-rather than other RAS pathway mutations, may be associated with adverse outcomes in pediatric B‑ALL, warranting further validation. Trial registration: The study was conducted with approval from the Institutional Review Board of Children’s Hospital of Soochow University (Approval number: 2019KS006).</p>

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The clinical relevance of RAS pathway gene mutations in childhood B-cell acute lymphoblastic leukemia

  • 期刊论文

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  • 发表日期：

    2026年7月13日

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  • Xiaoyu Chen,
  • Li Gao,
  • Yongping Zhang,
  • Yixin Hu,
  • Jian Pan,
  • Zhiheng Li,
  • Jun Lu,
  • Yizhen Li,
  • Shaoyan Hu

摘要

Objective: Notably, FLT3 and RAS pathway gene mutations represent a significant proportion of childhood B-cell acute lymphoblastic leukemia (B-ALL) cases. Our study explores whether these patients have distinct clinical features and prognostic outcomes. Methods: We retrospectively analyzed 488 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, and their cooperative effects. Results: 192 patients (39.3%) carried at least one RAS pathway alterations, while 76 patients (15.6%) 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 = 13.0, p < 0.001), NRAS and KRAS mutations (Phi coefficient = 0.19, χ² = 17.12, p < 0.0001), NRAS and PTPN11 (Phi coefficient = 0.138, χ² = 9.54, p = 0.0042). FLT3/NF1 co-mutated patients exhibited a higher frequency of abnormal karyotypes and had significantly poorer overall survival (OS) and event-free survival (EFS) (p < 0.05), particularly when compared to those without KMT2A rearrangements (p = 0.004 and p = 0.003, respectively). Collectively, RAS pathway alterations were not significantly associated with inferior OS or EFS. Multivariable Cox regression analysis confirmed that FLT3/NF1 co‑mutations were independently associated with inferior OS (HR = 12.39, 95% CI: 1.40-109.46, p = 0.024), and multivariable logistic regression analysis showed that they were also independently associated with Day 46 MRD ≥ 0.01% (OR = 9.50, 95% CI: 1.65–54.71, p = 0.01). Conclusion: Our findings suggest that FLT3/NF1 co-mutations-rather than other RAS pathway mutations, may be associated with adverse outcomes in pediatric B‑ALL, warranting further validation. Trial registration: The study was conducted with approval from the Institutional Review Board of Children’s Hospital of Soochow University (Approval number: 2019KS006).