High Mitochondrial DNA Stability in B-Cell Chronic Lymphocytic Leukemia

Abstract

BackgroundChronic Lymphocytic Leukemia (CLL) leads to progressive accumulation of lymphocytes in the blood, bone marrow, and lymphatic tissues. Previous findings have suggested that the mtDNA could play an important role in CLL.Methodology/Principal FindingsThe mitochondrial DNA (mtDNA) control-region was analyzed in lymphocyte cell DNA extracts and compared with their granulocyte counterpart extract of 146 patients suffering from B-Cell CLL; B-CLL (all recruited from the Basque country). Major efforts were undertaken to rule out methodological artefacts that would render a high false positive rate for mtDNA instabilities and thus lead to erroneous interpretation of sequence instabilities. Only twenty instabilities were finally confirmed, most of them affecting the homopolymeric stretch located in the second hypervariable segment (HVS-II) around position 310, which is well known to constitute an extreme mutational hotspot of length polymorphism, as these mutations are frequently observed in the general human population. A critical revision of the findings in previous studies indicates a lack of proper methodological standards, which eventually led to an overinterpretation of the role of the mtDNA in CLL tumorigenesis.Conclusions/SignificanceOur results suggest that mtDNA instability is not the primary causal factor in B-CLL. A secondary role of mtDNA mutations cannot be fully ruled out under the hypothesis that the progressive accumulation of mtDNA instabilities could finally contribute to the tumoral process. Recommendations are given that would help to minimize erroneous interpretation of sequencing results in mtDNA studies in tumorigenesis.

Mitochondrial DNA Alterations and Oxidative Stress in Acute Leukemia

“…In contrast, our data don't support the existence of any link between mtDNA mutations and acute leukemia. Such conclusions have also been recently drawn by Cerezo et al (2009) [10] from their study on B-cell CLL. While we detected a single significant difference at the position 343 between patients and healthy controls in PBMC, the epithelial buccal cells of patients, a nonmalignant tissue, also displayed the same C nucleotide in the homoplasmic state; this indicates that this mutation was not segregated in tumoral cells.…”

“…Several laboratories also reported the presence of mtDNA mutations in chronic lymphocytic (CLL) and myeloid (CML) leukemia and in acute lymphoblastic (ALL) and myeloid (AML) leukemia [7][8][9]. However, a recent study challenged the potential role of mtDNA mutations in leukemogenesis [10].…”

Mitochondrial DNA Copy Number and Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Risk in Two Prospective Studies

“…Since male smokers had a lower baseline mtDNA CN, and male smokers with higher mtDNA CN were at increased risk of CLL/SLL, these individuals may have genomic characteristics that are ideal for CLL/SLL development. Mitochondrial DNA genomes from CLL/SLL patients contain high levels of mtDNA content (29), are very stable, and can create genomic copies with deletions and mutations (30) without undergoing apoptosis or senescence.…”

Reconstructing ancient mitochondrial DNA links between Africa and Europe

“…Detailed information concerning the geographical origin of the grandparents was collected in order to exclude individuals whose ancestors arrived from Africa just recently (see Supplemental Data S1 for more details on the geographic origin of the donors). DNA extraction, PCR, and sequencing were performed as described in Cerezo et al (2009).…”