Decoding mitochondrial genes in pediatric AML and development of a novel prognostic mitochondrial gene signature

Abstract

Background: Gene expression profile of mitochondrial-related genes is not well deciphered in pediatric acute myeloid leukaemia (AML). We aimed to identify mitochondria-related differentially expressed genes (DEGs) in pediatric AML with their prognostic significance. Methods: Children with de novo AML were included prospectively between July 2016-December 2019. Transcriptomic profiling was done for a subset of samples, stratified by mtDNA copy number. Top mitochondria-related DEGs were identified and validated by real-time PCR. A prognostic gene signature risk score was formulated using DEGs independently predictive of overall survival (OS) in multivariable analysis. Predictive ability of the risk score was estimated along with external validation in The Tumor Genome Atlas (TCGA) AML dataset. Results: In 143 children with AML, twenty mitochondria-related DEGs were selected for validation, of which 16 were found to be significantly dysregulated. Upregulation of SDHC (p<0.001), CLIC1 (p=0.013) and downregulation of SLC25A29 (p<0.001) were independently predictive of inferior OS, and included for developing prognostic risk score. The risk score model was independently predictive of survival over and above ELN risk categorization (Harrell's c-index: 0.675). High-risk patients (risk score above median) had significantly inferior OS (p<0.001) and event free survival (p<0.001); they were associated with poor-risk cytogenetics (p=0.021), ELN intermediate/poor risk group (p=0.016), absence of RUNX1-RUNX1T1 (p=0.027), and not attaining remission (p=0.016). On external validation, the risk score also predicted OS (p=0.019) in TCGA dataset. Conclusion: We identified and validated mitochondria-related DEGs with prognostic impact in pediatric AML and also developed a novel 3-gene based externally validated gene signature predictive of survival.

Mitochondrial gene expression signature predicts prognosis of pediatric acute myeloid leukemia patients

“…Recent study by Erdem et al has also reported that FLT3-ITD + AML have high mitochondrial complex II(SDH) activity and inhibition of SDH complex enhance apoptosis of FLT3-ITD + AML cells in vitro as well as in vivo (53). We also observed that the overall activity of mitochondrial electron transport chain complex II was significantly higher in bone marrow mononuclear cells of pediatric AML patients compared to controls (21). This suggests mitochondrial complex II can be explored as a potential therapeutic target for AML in future studies.…”

“…Furthermore, using proteomic analysis, a recent study by Jayavelu et al reported that AML subgroup with high mitochondrial protein expression have shorter remission and poor survival outcomes in adult AML (20). However, there is only limited data on mitochondria-related gene expression profile and its impact on disease outcome of pediatric AML (21,22).…”