Low CADPS Expression Predicts Poor Outcomes in Fusion-Negative Pediatric Acute Lymphoblastic Leukemia

A Closer Look at Pediatric Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is one of the most common blood cancers in children. Thanks to advances in therapy, survival rates now exceed 90%. Despite this progress, some children still relapse, and for them, outcomes remain poor.

Genetics play a crucial role in classifying ALL and predicting prognosis. Fusion genes—created when two genes abnormally combine—are well-established markers. They are used for diagnosis, risk assessment, and guiding treatment choices. The World Health Organization now includes dozens of these fusions in its classification of leukemia, and clinical guidelines incorporate them into risk stratification.

Yet, not all children with ALL carry fusion genes. In fact, around 40% of pediatric ALL cases are fusion gene–negative (FG-negative). For this group, doctors lack reliable biomarkers to predict which patients are at greater risk of relapse. This gap leaves many families facing uncertainty in treatment decisions.

The Goal of the Study

Researchers from Shengjing Hospital of China Medical University and Chigene Translational Medical Research Center focused on FG-negative pediatric ALL. They aimed to uncover molecular signatures that could help identify high-risk patients.

To do this, they analyzed 54 FG-negative cases from their hospital using whole-exome and RNA sequencing. They then validated their findings with a larger public dataset from the TARGET ALL Phase II cohort, which included 203 patient samples.

What They Found

1. Mutations Are Not Enough

Genetic mutations, such as those in NRAS or KRAS, were common but showed no significant link to relapse. Tumor mutational burden also offered no predictive value.

2. CADPS Expression Stands Out

When comparing gene expression profiles, the team found CADPS (calcium-dependent activator protein for secretion) was consistently lower in patients who relapsed. CADPS has been described as a tumor suppressor in other cancers, and its downregulation here suggested a similar role in leukemia.

3. Validation in a Larger Cohort

Analysis of the TARGET dataset confirmed that low CADPS expression was linked to shorter event-free and overall survival. Importantly, CADPS remained an independent prognostic factor even after accounting for other clinical variables.

4. Prognostic Model With High Accuracy

Using CADPS expression together with clinical features such as age and white blood cell count, the researchers built a prediction model. For FG-negative patients, the model achieved strong accuracy, with AUC values of 0.804, 0.840, and 0.943 at 3, 5, and 10 years. This means CADPS levels could help predict survival with high reliability.

5. Pathways and Drug Sensitivity

Further analysis showed that patients with low CADPS had activation of pathways linked to cell growth and proliferation, such as E2F, mTORC1, and IL6-JAK-STAT3 signaling. Drug sensitivity predictions suggested that high-risk patients might respond better to certain therapies, including AZD6738, Dactinomycin, Trametinib, and Ulixertinib.

Implications for the Field

This study highlights CADPS as a promising biomarker for children with FG-negative ALL. Unlike genetic mutations, CADPS expression provides clear prognostic information. If confirmed in larger studies, it could help clinicians:

• Identify high-risk patients more accurately.

• Adapt treatment intensity based on CADPS levels.

• Explore targeted therapies guided by drug sensitivity predictions.

Limitations and Next Steps

The authors acknowledge several limitations:

• The relapse group was small (10 patients).

• The study was retrospective and single-center.

• Long-term follow-up data were limited.

• Functional experiments to confirm CADPS’s biological role in leukemia were not included.

Future research should validate these results in larger, prospective cohorts and explore the mechanisms by which CADPS affects leukemia progression and treatment response.

Conclusion

This study is the first to show that CADPS expression predicts prognosis in FG-negative pediatric ALL. Children with low CADPS levels had a higher risk of relapse and poorer survival. By integrating CADPS into prognostic models, researchers were able to achieve highly accurate predictions of clinical outcomes.

In pediatric oncology, where precision medicine is increasingly important, CADPS offers a potential tool to improve risk stratification and guide therapy in a group of patients who currently lack reliable markers.