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Cobaleda, C., Gutierrez-Cianca, N., Perez-Losada, J., Flores, T., Garcia-Sanz, R., Gonzalez, M., et al. (2000). A primitive hematopoietic cell is the target for the leukemic transformation in human philadelphia-positive acute lymphoblastic leukemia. Blood, 95(3), 1007–1013.
Abstract: BCR-ABL is a chimeric oncogene generated by translocation of sequences from the chromosomal counterpart (c-ABL gene) on chromosome 9 into the BCR gene on chromosome 22. Alternative chimeric proteins, BCR-ABL(p190) and BCR-ABL(p210), are produced that are characteristic of chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(1)-ALL). In CML, the transformation occurs at the level of pluripotent stem cells. However, Ph(1)-ALL is thought to affect progenitor cells with lymphoid differentiation. Here we demonstrate that the cell capable of initiating human Ph(1)-ALL in non-obese diabetic mice with severe combined immunodeficiency disease (NOD/SCID), termed SCID leukemia-initiating cell (SL-IC), possesses the differentiative and proliferative capacities and the potential for self-renewal expected of a leukemic stem cell. The SL-ICs from all Ph(1)-ALL analyzed, regardless of the heterogeneity in maturation characteristics of the leukemic blasts, were exclusively CD34(+ )CD38(-), which is similar to the cell-surface phenotype of normal SCID-repopulating cells. This indicates that normal primitive cells, rather than committed progenitor cells, are the target for leukemic transformation in Ph(1)-ALL.
Keywords: ADP-ribosyl Cyclase; Animals; Antigens, CD/analysis; Antigens, CD34/analysis; Antigens, CD38; Antigens, Differentiation/analysis; Antigens, Neoplasm/analysis; Cell Differentiation; Cell Division; Cell Transformation, Neoplastic/*pathology; Fusion Proteins, bcr-abl/physiology; Hematopoietic Stem Cells/classification/*pathology; Humans; Immunophenotyping; Membrane Glycoproteins; Mice; Mice, Inbred NOD; Mice, SCID; NAD+ Nucleosidase/analysis; Neoplasm Transplantation; Neoplastic Stem Cells/classification/*pathology/transplantation; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*pathology
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Henderson, M. J., Choi, S., Beesley, A. H., Sutton, R., Venn, N. C., Marshall, G. M., et al. (2008). Mechanism of relapse in pediatric acute lymphoblastic leukemia. Cell Cycle, 7(10), 1315–1320.
Abstract: Relapse following initial chemotherapy remains a barrier to survival in approximately 20% of children suffering from acute lymphoblastic leukemia (ALL). Recently, to investigate the mechanism of relapse, we analysed clonal populations in 27 pairs of matched diagnosis and relapse ALL samples using PCR-based detection of multiple antigen receptor gene rearrangements. These clonal markers revealed the emergence of apparently new populations at relapse in 13 patients. In those cases where the new 'relapse clone' could be detected in the diagnosis population, there was a close correlation between length of first remission and quantity of the relapse clone in the diagnosis sample. A shorter length of time to first relapse correlated with a higher quantity of the relapsing clone at diagnosis. This observation, together with demonstrated differential chemosensitivity between sub-clones at diagnosis, indicates that relapse in ALL patients may commonly involve selection of a minor intrinsically resistant sub-clone that is undetectable by routine PCR-based methods. From a clinical perspective, relapse prediction may be improved with strategies to detect minor potentially resistant sub-clones early during treatment, hence allowing intensification of therapy. Together with the availability of relevant in vivo experimental models and powerful technology for detailed analysis of patient specimens, this new information will help shape future experimentation towards targeted therapy for high-risk ALL.
Keywords: Child; *Drug Resistance, Neoplasm; Gene Rearrangement/*genetics; Genetic Markers/genetics; Humans; Models, Biological; Polymerase Chain Reaction; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*diagnosis/drug therapy/*prevention & control; Receptors, Antigen/genetics; Recurrence; Time Factors
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Focke, F., Schuermann, D., Kuster, N., & Schär, P. (2010). DNA fragmentation in human fibroblasts under extremely low frequency electromagnetic field exposure. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 683(1-2), 74–83.
Abstract: Extremely low frequency electromagnetic fields (ELF-EMFs) were reported to affect DNA integrity in human cells with evidence based on the Comet assay. These findings were heavily debated for two main reasons; the lack of reproducibility, and the absence of a plausible scientific rationale for how EMFs could damage DNA. Starting out from a replication of the relevant experiments, we performed this study to clarify the existence and explore origin and nature of ELF-EMF induced DNA effects. Our data confirm that intermittent (but not continuous) exposure of human primary fibroblasts to a 50 Hz EMF at a flux density of 1 mT induces a slight but significant increase of DNA fragmentation in the Comet assay, and we provide first evidence for this to be caused by the magnetic rather than the electric field. Moreover, we show that EMF-induced responses in the Comet assay are dependent on cell proliferation, suggesting that processes of DNA replication rather than the DNA itself may be affected. Consistently, the Comet effects correlated with a reduction of actively replicating cells and a concomitant increase of apoptotic cells in exposed cultures, whereas a combined Fpg-Comet test failed to produce evidence for a notable contribution of oxidative DNA base damage. Hence, ELF-EMF induced effects in the Comet assay are reproducible under specific conditions and can be explained by minor disturbances in S-phase processes and occasional triggering of apoptosis rather than by the generation of DNA damage.
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Wolf, C. (2008). Security considerations in blinded exposure experiments using electromagnetic waves. Bioelectromagnetics, 29(8), 658–659.
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Kuster, N., & Schönborn, F. (2000). Recommended minimal requirements and development guidelines for exposure setups of bio-experiments addressing the health risk concern of wireless communications. Bioelectromagnetics, 21(7), 508–514.
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