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      Mitochondrial concept of leukemogenesis: key role of oxygen-peroxide effects

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          Abstract

          Background and hypothesis

          The high sensitivity of hematopoietic cells, especially stem cells, to radiation and to pro-oxidative and other leukemogenic agents is related to certain of their morphological and metabolic features. It is attributable to the low (minimal) number of active mitochondria and the consequently slow utilization of O 2 entering the cell. This results in an increased intracellular partial pressure of O 2 (pO 2) and increased levels of reactive oxygen (ROS) and nitrogen (RNS) species, and a Δ(PO – AO) imbalance between the pro-oxidative (PO) and antioxidative (AO) constituents.

          Proposed mechanism

          Because excessive O 2 is toxic, we suggest that hematopoietic cells exist in a kind of unstable dynamic balance. This suggestion is based on the idea that mitochondria not only consume O 2 in the process of ATP production but also constitute the main anti-oxygenic stage in the cell's protective antioxidative system. Variations in the mitochondrial base capacity (quantity and quality of mitochondria) constitute an important and highly efficient channel for regulating the oxidative stress level within a cell.

          The primary target for leukemogenic agents is the few mitochondria within the hematopoietic stem cell. Disturbance and weakening of their respiratory function further enhances the initial pro-oxidative state of the cell. This readily results in peroxygenation stress, creating the necessary condition for inducing leukemogenesis. We propose that this is the main cause of all related genetic and other disorders in the cell. ROS, RNS and peroxides act as signal molecules affecting redox-sensitive transcription factors, enzymes, oncogenes and other effectors. Thereby, they influence the expression and suppression of many genes, as well as the course and direction of proliferation, differentiation, leukemogenesis and apoptosis.

          Differentiation of leukemic cells is blocked at the precursor stage. While the transformation of non-hematopoietic cells into tumor cells starts during proliferation, hematopoietic cells become leukemic at one of the interim stages in differentiation, and differentiation does not continue beyond that point. Proliferation is switched to differentiation and back according to a trigger principle, again involving ROS and RNS. When the leukemogenic Δ L(PO – AO) imbalance decreases in an under-differentiated leukemia cell to the differentiation level Δ D(PO – AO), the cell may continue to differentiate to the terminal stage.

          Conclusion

          The argument described in this article is used to explain the causes of congenital and children's leukemia, and the induction of leukemia by certain agents (vitamin K3, benzene, etc.). Specific research is required to validate the proposals made in this article. This will require accurate and accessible methods for measuring and assessing oxidative stress in different types of cells in general, and in hematopoietic cells in particular, in their different functional states.

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          Most cited references 53

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          Oxidative stress and gene regulation.

          Reactive oxygen species are produced by all aerobic cells and are widely believed to play a pivotal role in aging as well as a number of degenerative diseases. The consequences of the generation of oxidants in cells does not appear to be limited to promotion of deleterious effects. Alterations in oxidative metabolism have long been known to occur during differentiation and development. Experimental perturbations in cellular redox state have been shown to exert a strong impact on these processes. The discovery of specific genes and pathways affected by oxidants led to the hypothesis that reactive oxygen species serve as subcellular messengers in gene regulatory and signal transduction pathways. Additionally, antioxidants can activate numerous genes and pathways. The burgeoning growth in the number of pathways shown to be dependent on oxidation or antioxidation has accelerated during the last decade. In the discussion presented here, we provide a tabular summary of many of the redox effects on gene expression and signaling pathways that are currently known to exist.
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            Chromosome translocations and covert leukemic clones are generated during normal fetal development.

            Studies on monozygotic twins with concordant leukemia and retrospective scrutiny of neonatal blood spots of patients with leukemia indicate that chromosomal translocations characteristic of pediatric leukemia often arise prenatally, probably as initiating events. The modest concordance rate for leukemia in identical twins ( approximately 5%), protracted latency, and transgenic modeling all suggest that additional postnatal exposure and/or genetic events are required for clinically overt leukemia development. This notion leads to the prediction that chromosome translocations, functional fusion genes, and preleukemic clones should be present in the blood of healthy newborns at a rate that is significantly greater than the cumulative risk of the corresponding leukemia. Using parallel reverse transcriptase-PCR and real-time PCR (Taqman) screening, we find that the common leukemia fusion genes, TEL-AML1 or AML1-ETO, are present in cord bloods at a frequency that is 100-fold greater than the risk of the corresponding leukemia. Single-cell analysis by cell enrichment and immunophenotype/fluorescence in situ hybridization multicolor staining confirmed the presence of translocations in restricted cell types corresponding to the B lymphoid or myeloid lineage of the leukemias that normally harbor these fusion genes. The frequency of positive cells (10(-4) to 10(-3)) indicates substantial clonal expansion of a progenitor population. These data have significant implications for the pathogenesis, natural history, and etiology of childhood leukemia.
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              The expression of mitochondrial DNA transcription factors during early cardiomyocyte in vitro differentiation from human embryonic stem cells.

              Mitochondrial biogenesis and activation of both oxidative phosphorylation, as well as transcription and replication of the mitochondrial genome, are key regulatory events in cell differentiation. Mitochondrial DNA transcription and replication are highly dependent on the interaction with nuclear-encoded transcription factors translocated from the nucleus. Using a human embryonic stem cell line, HSF 6, we analyzed the proliferation of mitochondria and the expression of mtDNA-specific transcription factors in undifferentiated, migratory embryonic stem cells and spontaneously derived cardiomyocytes. Mitochondrial proliferation and mtDNA transcription are initiated in human embryonic stem cells as they undergo spontaneous differentiation in culture into beating cardiomyocytes. Undifferentiated, pluripotent human embryonic stem cells have few mitochondria, and, as they differentiate, they polarize to one extremity of the cell and then bipolarize the differentiating cell. The differentiated cell then adopts the cytoplasmic configuration of a somatic cell as evidenced in differentiating cardiomyocytes. Transcription and replication of the extranuclear mitochondrial genome is dependent on nuclear encoded factors exported to the mitochondrion. However, the differentiating cardiomyocytes have reduced or absent levels of these transcription and replication factors, namely mitochondrial transcription factors A, B1, B2, and nuclear respiratory factor 1 and polymerase gamma. Therefore, final embryonic stem cell commitment may be influenced by mitochondrial proliferation and mtDNA transcription. However, it is likely that differentiating cardiomyocytes are in mitochondrial arrest, awaiting commitment to a final cell fate.
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                Author and article information

                Journal
                Theor Biol Med Model
                Theoretical Biology & Medical Modelling
                BioMed Central
                1742-4682
                2008
                11 November 2008
                : 5
                : 23
                Affiliations
                [1 ]Scientific Center for Anti-Infectious Drugs, Almaty, Kazakhstan
                Article
                1742-4682-5-23
                10.1186/1742-4682-5-23
                2614412
                19014456
                Copyright © 2008 Lyu et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Categories
                Review

                Quantitative & Systems biology

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