Pediatric Acute Lymphoblastic Leukemia: Understanding CADPS as a Prognostic Marker for High-Risk Patients

Acute lymphoblastic leukemia (ALL) is a type of blood cancer that predominantly affects children. Thanks to improvements in treatments, survival rates for ALL have risen dramatically, now exceeding 90%. However, a significant challenge remains: some children relapse after initial treatment, and for them, the outlook is much less promising.

ALL is classified based on genetic mutations, particularly fusion genes, which occur when two genes abnormally join. These genetic fusions serve as important markers for diagnosis, risk assessment, and treatment decisions. While the World Health Organization has recognized numerous fusion genes in its leukemia classification, nearly 40% of pediatric ALL cases do not carry any fusion genes (referred to as fusion gene-negative or FG-negative). For these patients, doctors have limited tools to predict which children are at higher risk for relapse, creating uncertainty for clinicians and families when making treatment decisions.

Key Findings from Recent Research

A team from Shengjing Hospital of China Medical University and Chigene Translational Medical Research Center sought to address this gap by investigating molecular markers that could help predict relapse in FG-negative pediatric ALL. They analyzed data from 54 FG-negative ALL patients, using whole-exome sequencing and RNA sequencing, and validated their findings with a larger cohort of 203 patients from the TARGET ALL Phase II dataset.

The study revealed the following key findings:

1. Genetic Mutations Alone Are Not Predictive

Although mutations in genes like NRAS and KRAS were common, they did not correlate with relapse. Similarly, tumor mutational burden did not provide useful predictive information for patient outcomes.

2. CADPS Expression as a Key Prognostic Factor

The most striking finding was the low expression of CADPS (calcium-dependent activator protein for secretion) in patients who relapsed. CADPS is known as a tumor suppressor in other cancers, and its downregulation suggests a similar role in leukemia.

3. Validation and Accuracy

The analysis of the TARGET dataset confirmed that low CADPS expression was associated with poorer survival outcomes. Notably, CADPS expression remained a significant predictor of prognosis even when other clinical factors were considered. The researchers also developed a prognostic model combining CADPS expression with clinical features (such as age and white blood cell count). This model showed high accuracy in predicting long-term survival, with AUC values reaching 0.804, 0.840, and 0.943 at 3, 5, and 10 years, respectively.

4. Potential for Targeted Therapies

Further analysis revealed that patients with low CADPS expression showed activation of key pathways involved in cell growth and proliferation, such as E2F, mTORC1, and IL6-JAK-STAT3 signaling. This information could guide drug sensitivity predictions, suggesting that these high-risk patients might benefit from targeted therapies, including AZD6738, Dactinomycin, Trametinib, and Ulixertinib.

Importance and Potential Impact

This study underscores the potential of CADPS expression as a reliable biomarker for predicting outcomes in children with FG-negative ALL. Unlike genetic mutations, which often fail to predict relapse in this group, CADPS levels offer clear prognostic information. If validated in larger studies, CADPS could help clinicians:

• More accurately identify high-risk patients: CADPS levels can differentiate patients with higher chances of relapse, allowing for tailored treatment plans.
• Adjust treatment intensity: Based on CADPS expression, doctors may be able to intensify treatment for high-risk patients or avoid unnecessary treatments for those at low risk.
• Guide personalized therapies: Drug sensitivity predictions could open the door to more effective, targeted therapies for high-risk patients.

Limitations and Challenges

Despite these promising findings, the study has several limitations:

• Small sample size: The relapse group consisted of only 10 patients, limiting the generalizability of the results.
• Retrospective and single-center design: The study's findings were based on data collected retrospectively from a single institution. Prospective, multi-center studies are needed to confirm the results.
• Lack of functional experiments: The study did not include functional experiments to confirm CADPS's direct role in leukemia progression or treatment response.
• Limited follow-up: Long-term follow-up data were unavailable, which may impact the durability of CADPS as a prognostic marker.

Future research should aim to validate these findings in larger, prospective cohorts and explore the mechanisms through which CADPS influences leukemia progression. Further functional studies are also needed to confirm how CADPS may contribute to treatment resistance or sensitivity.

Conclusion

This research marks an important step toward improving the prognosis of children with fusion gene-negative acute lymphoblastic leukemia. By identifying CADPS expression as a key prognostic marker, the study provides a foundation for more accurate risk stratification and personalized treatments. As the field of pediatric oncology moves toward precision medicine, CADPS could become an invaluable tool in guiding treatment decisions, ultimately helping to improve survival rates for this high-risk group of patients.

More information:

Bin Zhang et al, Low expression of CADPS predicts poor prognosis in pediatric acute lymphoblastic leukemia without fusion genes. Biomol Biomed [Internet]. 2025 May 30 [cited 2025 Dec. 4];25(10):2295–2307.

Available from: https://doi.org/10.17305/bb.2025.12254

Journal information: Biomolecules and Biomedicine

Provided by: Association of Basic Medical Sciences of FBIH

Provided by Association of Basic Medical Sciences of FBIH