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Proteomic Signatures and Early Biomarkers Predicting Veno-Occlusive Disease in Pediatric Patients Undergoing
Kyung Taek Hong1, Suwan Yu2, Jin Woo Jung3
1Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, Republic of Korea; Seoul National University Cancer Research Institute, Seoul, Republic of Korea.
Hepatic veno-occlusive disease (VOD), or sinusoidal obstruction syndrome, is a life-threatening complication following hematopoietic cell transplantation (HSCT). In pediatric patients, busulfan-based myeloablative conditioning is a major risk factor. This study aimed to identify plasma proteomic biomarkers predictive of VOD development in children undergoing haploidentical HSCT with busulfan-based conditioning and post-transplant cyclophosphamide (PTCy). Plasma samples were collected from 51 children (VOD, n = 26; control, n = 25) at baseline and 1 to 4 h postbusulfan infusion on days -8 to -5. Proteomic profiles using liquid chromatography-tandem mass spectrometry identified 720 proteins. Differential abundance, longitudinal clustering, pathway enrichment, and machine learning-based biomarker selection were performed. The VOD group exhibited predominantly down-regulated proteins, with minimal changes from baseline during early treatment. Pathway enrichment analysis revealed distinct temporal patterns between the groups. At baseline, the VOD group showed enrichment in homeostasis-related pathways, while detoxification pathways were persistently activated postconditioning. In contrast, the control group demonstrated early activation of detoxification pathways, which gradually declined, suggesting effective oxidative stress management. A machine learning model, trained on a discovery cohort (70%) and 30% validated on a separate cohort (30%), identified 15 biomarkers. Notably, glutamate-cysteine ligase catalytic subunit (GCLC), crucial for glutathione biosynthesis, and fructose-bisphosphatase 1 (FBP1), a gluconeogenic enzyme, were down-regulated at baseline in the VOD group. Baseline down-regulation of proteins such as GCLC and FBP1 may serve as early biomarkers for predicting VOD, facilitating timely prophylactic interventions in high-risk pediatric patients undergoing haploidentical HSCT with busulfan-based conditioning and PTCy.
Hepatic veno-occlusive disease (VOD), or sinusoidal obstruction syndrome, is a life-threatening complication following hematopoietic cell transplantation (HSCT). In pediatric patients, busulfan-based myeloablative conditioning is a major risk factor. This study aimed to identify plasma proteomic biomarkers predictive of VOD development in children undergoing haploidentical HSCT with busulfan-based conditioning and post-transplant cyclophosphamide (PTCy). Plasma samples were collected from 51 children (VOD, n = 26; control, n = 25) at baseline and 1 to 4 h postbusulfan infusion on days -8 to -5. Proteomic profiles using liquid chromatography-tandem mass spectrometry identified 720 proteins. Differential abundance, longitudinal clustering, pathway enrichment, and machine learning-based biomarker selection were performed. The VOD group exhibited predominantly down-regulated proteins, with minimal changes from baseline during early treatment. Pathway enrichment analysis revealed distinct temporal patterns between the groups. At baseline, the VOD group showed enrichment in homeostasis-related pathways, while detoxification pathways were persistently activated postconditioning. In contrast, the control group demonstrated early activation of detoxification pathways, which gradually declined, suggesting effective oxidative stress management. A machine learning model, trained on a discovery cohort (70%) and 30% validated on a separate cohort (30%), identified 15 biomarkers. Notably, glutamate-cysteine ligase catalytic subunit (GCLC), crucial for glutathione biosynthesis, and fructose-bisphosphatase 1 (FBP1), a gluconeogenic enzyme, were down-regulated at baseline in the VOD group. Baseline down-regulation of proteins such as GCLC and FBP1 may serve as early biomarkers for predicting VOD, facilitating timely prophylactic interventions in high-risk pediatric patients undergoing haploidentical HSCT with busulfan-based conditioning and PTCy.
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