Platelet transfusion can mimic somatic mtDNA mutations

Meierhofer, David; Ebner, Sabine; Mayr, Johannes A.; Jones, Neil D.; Kofler, Barbara; Sperl, Wolfgang

doi:10.1038/sj.leu.2404070

Cited by 9 publications

(11 citation statements)

References 5 publications

(13 reference statements)

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“…mtDNA is more amenable to mutations than nuclearDNA (nDNA) because it lacks the chromatin organization of nDNA [28]. Although chemotherapy was shown to induce heterotrophic mtDNA mutations in CLL [29], Meierhofer et al found that blood transfusions might have ‘contaminated’ the tested samples with donors’ blood cell mitochondria [30] harboring abnormalities in hot spots that are frequently mutated in the general population [31]. Nevertheless, although the mtDNA structure of patients with CLL is no different from that of normal individuals, several studies showed that an increase in mtDNA copy numbers is associated with an increased risk for the development of CLL and non-Hodgkin’s Lymphoma [32,33].…”

Section: Oxidative Phosphorylation In Cllmentioning

confidence: 99%

Metabolism pathways in chronic lymphocytic leukemia

Rozovski

Hazan‐Halevy

Barzilai

et al. 2015

Leukemia & Lymphoma

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Alterations in CLL cell metabolism have been studied by several investigators. Unlike normal B lymphocytes or other leukemia cells, CLL cells, like adipocytes, store lipids and utilize free fatty acids (FFA) to produce chemical energy. None of the recently identified mutations in CLL directly affects metabolic pathways, suggesting that genetic alterations do not directly contribute to CLL cells’ metabolic reprogramming. Conversely, recent data suggest that activation of STAT3 or downregulation of microRNA-125 levels plays a crucial role in the utilization of FFA to meet CLL cells’ metabolic needs. STAT3, known to be constitutively activated in CLL, increases the levels of lipoprotein lipase that mediates lipoprotein uptake and shifts CLL cells’ metabolism towards utilization of FFA. Herein we review the evidence for altered lipid metabolism, increased mitochondrial activity, and formation of reactive oxygen species in CLL cells, and discuss possible therapeutic strategies to inhibit lipid metabolism pathways in patient with CLL.

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Section: Oxidative Phosphorylation In Cllmentioning

confidence: 99%

Metabolism pathways in chronic lymphocytic leukemia

Rozovski

Hazan‐Halevy

Barzilai

et al. 2015

Leukemia & Lymphoma

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“…According to these authors, chemotherapy with DNA-damaging agents could cause mtDNA mutations in primary leukemia cells, which often exist in heteroplasmic condition. These findings were later put into question by Meierhofer et al [11], who showed that platelet transfusion can mimic somatic mtDNA mutations. He et al [12] sequenced the entire mtDNA from both normal tissue (buccal epithelial cells) and cells extracted from bone marrow in 24 patients with adult-onset leukemia.…”

Section: Introductionmentioning

confidence: 99%

High Mitochondrial DNA Stability in B-Cell Chronic Lymphocytic Leukemia

et al. 2009

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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.

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“…Notable also is the presence of 3 mutations in the 2 consensus sequence types in UPN22, without evidence of intermediary types with single or double mutations; this patient had received a platelet transfusion proximate to sample acquisition, and contamination by donor blood cells cannot be excluded, as has been reported in a patient with ALL. 35 In any case, mutations at sites 16320 and 195 and other mutations that stepped from the consensus sequence 16222-16519-263-319 in the majority of single cells in patient UPN22 were obviously the product of a quick mutation process.…”

Section: Mtdna Mutation Process In Leukemiamentioning

confidence: 99%