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

Shilpi Chaudhary; Shuvadeep Ganguly; Jayanth Kumar Palanichamy; Archna Singh; Dibyabhaba Pradhan; Radhika Bakhshi; Anita Chopra; Sameer Bakhshi

doi:10.3389/fonc.2023.1109518

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

Front Oncol. 2023 Feb 9:13:1109518. doi: 10.3389/fonc.2023.1109518. eCollection 2023.

Authors

Shilpi Chaudhary¹, Shuvadeep Ganguly¹, Jayanth Kumar Palanichamy², Archna Singh², Dibyabhaba Pradhan³, Radhika Bakhshi⁴, Anita Chopra⁵, Sameer Bakhshi¹

Affiliations

¹ Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India.
² Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India.
³ Computational Genomics Centre, Indian Council of Medical Research (ICMR), New Delhi, India.
⁴ Shaheed Rajguru College of Applied Sciences for Women, University of Delhi, Delhi, India.
⁵ Department of Laboratory Oncology, All India Institute of Medical Sciences, New Delhi, India.

Abstract

Introduction: 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.

Discussion: 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.

Keywords: RNA sequencing; acute myeloid leukema; child; gene signature; mitochondria.

Grants and funding

The authors acknowledge the funding support from DST-SERB (Department of Science and Technology - Science and Engineering Research Board), Government of India for this work. (Extramural Research grant: EMR/2016/006376 and CRG/2021/001887). The authors also acknowledge the funding support from ICMR (Indian Council of Medical Research), Government of India for this work (ICMR SRF: 2019-6059/CMB/BMS).