EXPLORING THE MUTATIONAL LANDSCAPE OF MITOCHONDRIAL GENOME IN HEMATOLOGIC MALIGNANCIES
Mitochondria are key regulators of energy metabolism, apoptosis, and redox signaling, and their genome (mtDNA) is particularly vulnerable to genomic alterations due to its proximity to the respiratory chain, lack of protective histones, and limited repair capacity. Although mtDNA mutations have been implicated in carcinogenesis, their contribution to hematologic malignancies remains insufficiently understood, particularly with respect to low-level heteroplasmic variants. In this study, we analyzed 728 whole-genome and whole-exome sequencing samples from patients with diffuse large B-cell lymphoma (DLBCL), acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL), alongside two cohorts of healthy donors. We identified 21, 19, and 16 disease-specific heteroplasmic mtDNA missense mutations in DLBCL, AML, and CLL, respectively. These alterations frequently recurred in both tumor and matched normal counterparts, but were absent in healthy individuals, indicating a potential disease-associated signature. DLBCL exhibited a uniformly high burden of mitochondrial mutations, independent of nuclear alterations, while AML patients could be stratified into subgroups based on mtDNA mutational burden, with increased damage correlating with poorer overall survival. Furthermore, co-occurrence of mtDNA variants with DNMT3A mutations in AML suggested possible nuclear-mitochondrial interactions. Targeted mitochondrial sequencing in cell lines validated recurrent variants and confirmed accurate detection of heteroplasmy levels. Finally, analysis of T lymphocytes isolated from DLBCL patients revealed the presence of disease-specific mtDNA mutations in non-neoplastic immune effector cells, suggesting potential implications for immune surveillance. Together, these findings provide the first systematic characterization of mtDNA alterations across major hematologic malignancies. They highlight the widespread disruption of the mitochondrial genome, not only in tumor cells but also in immune compartments, with potential relevance for prognosis, therapeutic response, and immune regulation.
mitochondrial genetics, hematologic malignancies, mitochondrial DNA, Settore MEDS-02/A - Patologia generale
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