Implications of mitochondrial DNA variants in pediatric B-cell acute lymphoblastic leukemia

• Published in: Egyptian Journal of Medical Human Genetics Vol. 23; no. 1; pp. 1 - 11
• Main Authors: Jain, Ayushi, Katiyar, Amit, Singh, Ritika, Bakhshi, Sameer, Singh, Harpreet, Palanichamy, Jayanth Kumar, Singh, Archna
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.12.2022; Springer; Springer Nature B.V; SpringerOpen
• Subjects: Acute lymphoblastic leukemia; Acute lymphocytic leukemia; Bone marrow; Cancer; Comparative analysis; Copy number; Electron transport chain; Ethylenediaminetetraacetic acid; Genes; Genetic aspects; Genomes; Genomics; Leukemia; Lymphocytes B; Medicine; Medicine & Public Health; Mitochondrial DNA; Mitochondrial DNA variants; Next generation sequencing; Oxidative phosphorylation; Pathogenicity; Patients; Pediatrics; Peripheral blood; Tumors; Variation; India; Mitochondrial DNA; Acute lymphoblastic leukemia; Oxidative phosphorylation; Mitochondrial DNA variants; Next generation sequencing
• ISSN: 1110-8630; 2090-2441
• DOI: 10.1186/s43042-022-00347-0

Background Research on the role of variations in the mitochondrial genome in pathogenesis of acute lymphoblastic leukemia (ALL) has been unfolding at a rapid rate. Our laboratory has previously described higher number of copies of the mitochondrial genomes per cell in pediatric ALL patients as compared to the healthy controls. In the current study, we evaluated the pattern of mitochondrial genome variations in 20 de-novo pediatric B-ALL cases and seven controls. Quantitative real-time Polymerase Chain Reaction was used for estimation of mitochondrial genomes’ copy number in bone marrow samples of each ALL patient and peripheral blood samples of controls. The complete mitochondrial genomes of all samples were sequenced using the Illumina platform. Results Sequencing data analysis using multiple mitochondrial genome databases revealed 325 variants in all 27 samples, out of which 221 variants were previously known while 104 were unassigned, new variants. The 325 variants consisted of 7 loss-of-function variants, 131 synonymous variants, 75 missense variants, and 112 non-coding variants. New, missense variants ( n  = 21) were identified in genes encoding the electron transport chain complexes with most of them encoding ND4, ND5 of complex I. Missense and loss-of-function variants were found to be deleterious by many predictor databases of pathogenicity. MuTect2 identified true somatic variants present only in tumors between patient-sibling pairs and showed overlap with missense and loss-of-function variants. Online MtDNA-server showed heteroplasmic and homoplasmic variants in mitochondrial genome. Conclusions The data suggest that some of these variations might have a deleterious impact on the expression of mitochondrial encoded genes with a possible functional relevance in leukemia.