Distinct Mitochondrial DNA Deletion Profiles in Pediatric B- and T-ALL During Diagnosis, Remission, and Relapse

Background: Mitochondria are crucial for energy production and possess their own genome (mtDNA). While large mtDNA deletions cause primary mitochondrial diseases, their role in cancers remains understudied. Given that cancer is a metabolic disease, mtDNA deletions in tumors across disease stages may significantly impact disease etiology and treatment response.Objective: The aim of this study was to characterize mtDNA deletions in pediatric B-cell (B-ALL) and T-cell (T-ALL) acute lymphoblastic leukemia during diagnosis, remission, and relapse. We hypothesize that ALL subtypes exhibit distinct mtDNA deletion profiles, reflecting different etiologies, which may clarify the role of mitochondrial genetics in pediatric leukemia.Methods: Utilizing long-range PCR, next-generation sequencing, and the Splice-Break2 bioinformatics pipeline, we analyzed mtDNA deletion patterns of diagnostic, remission, and relapse samples from pediatric B-ALL and T-ALL patients. We assessed deletion frequency, size, breakpoint variations, and conducted statistical analyses based on ALL subtypes and disease stages.Results: Extensive mtDNA deletions were identified in both B-ALL and T-ALL samples, with significant variation across disease stages. T-ALL exhibited a higher frequency and larger size of mtDNA deletions than B-ALL, indicating greater mitochondrial instability that may contribute to its aggressiveness. In B-ALL, remission samples showed fewer and less variation in mtDNA deletions, with some cases showing large clonal deletions at remission, which suggests selection occurred during treatment. Clustering analysis revealed non-random deletion distributions within ALL subtypes, indicating selective pressures. Additionally, a case of a unique mtDNA deletion of high heteroplasmy during remission suggests treatment-induced mitochondrial toxicity may contribute to late effects in ALL survivors.