Mitophagy-Driven Prognosis in Pediatric Acute Myeloid Leukemia: A New Frontier

Abstract

Background: Mitophagy is a crucial mitochondrial quality control mechanism that removes dysfunctional mitochondria via lysosomal degradation, maintaining cellular homeostasis. Cancer cells exploit this process to sustain mitochondrial function, promote tumor renewal, and enhance therapy resistance. While mitophagy has been extensively studied in solid tumors, its role in Acute Myeloid Leukemia (AML), particularly in pediatric cases, remains largely unexplored. Therefore, this study investigated the prognostic value of pivotal mitophagy-related genes, PINK1, FUNDC1, and BNIP3, contributing to the flagging and recognition of damaged mitochondria. Methodology: Expression of PINK1, FUNDC1, and BNIP3 was analyzed using qRT-PCR in bone marrow samples from 90 pediatric AML patients and 30 controls. Kaplan-Meier survival analysis was performed to evaluate their association with overall survival (OS) and relapse-free survival (RFS) based on quartile expression. Pathway enrichment analysis was conducted using bioinformatics tools. Results: PINK1 (fold-change ~2.5, p = 0.0180) and FUNDC1 (fold-change ~4.0, p = 0.0335) were significantly upregulated in AML samples, with lower quartile expression of PINK1 strongly correlating with poor overall survival (OS) [Hazard Ratio (HR) = 3.636; 95% Confidence Interval (CI): 1.723–7.671; p = 0.0001]. Similarly, the lower quartile expression of FUNDC1 was associated with poor OS (HR = 2.027; 95% CI: 0.9474–4.339; p = 0.0384). Notably, BNIP3 expression did not differ significantly between pediatric AML and control samples (p = 0.769); however, higher quartile expression of BNIP3 was associated with poorer OS (HR = 3.238; 95% CI: 1.500–6.989; p = 0.0001). We did not observe the association of mitophagy-related genes with RFS. Pathway enrichment analysis revealed that PINK1 and FUNDC1 play key roles in mitophagy and hypoxia adaptation, while BNIP3 is primarily involved in apoptosis and cellular stress signaling. Conclusion: Overall, PINK1 and FUNDC1 may be potential prognostic biomarkers for OS in pediatric AML, emphasizing their role in mitochondrial homeostasis and leukemia progression. However, BNIP3 could also be used as prognostic markers; further validation on a large sample size is still required. This study will open a new AML diagnosis, prognosis, and therapy frontier.