Mitophagy-driven prognosis in pediatric acute myeloid leukemia: a new frontier.
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Mitophagy is a selective form of autophagy that plays a crucial role in mitochondrial quality control. Mediators of the mitophagy pathway have been reported to contribute to tumor progression in multiple solid tumors. Limited data suggests that the overexpression of certain pathway components may predict for adverse survival outcomes in adult AML. However, the role of these mediators in pediatric AML has not been studied previously. We identified nine mitophagy-related genes (PINK1, PARKIN, SQSTM1, NDP52, OPTN, ULK1, MAP1LC3B, FUNDC1, and BNIP3) using the Reactome pathway database and Ensembl genome browser. Gene expression for each of the nine genes was quantified using quantitative reverse transcription polymerase chain reaction on bone marrow mononuclear cells in a retrospective cohort of 90 children (aged ≤ 18 years) with AML and 30 controls. Differential expression of these genes between patients and controls and across different molecular subtypes was assessed using nonparametric statistical tests. For external validation, transcriptomic data from children and young adults (aged ≤ 39 years) with AML and control samples from the Beat AML cohort were also analyzed. Survival analyses were performed using Kaplan-Meier estimates, and log-rank tests were used to evaluate associations between gene expression (upper versus lower quartiles) and relapse-free and overall survival in our patient cohort. A total of 90 children with AML patients and 30 controls were included. All nine mitophagy-related genes were significantly overexpressed in AML compared with controls, which was independently confirmed in the Beat AML cohort. Upregulation of all nine genes was consistent across most subgroups examined. Among these genes, only FUNDC1 overexpression was significantly associated with inferior relapse-free survival (HR = 2.039, p = 0.044). Mitophagy-related genes are upregulated across pediatric AML subtypes. FUNDC1 expression overexpression is associated with inferior relapse-free survival (RFS). Identifying vulnerabilities in mitophagy pathways may open avenues for therapeutic targeting in pediatric AML.