Genomic alterations of DDR-associated genes including ATM, which regulates homologous recombination repair, were observed in almost half of NBs, suggesting that synthetic lethality could be induced by treatment with a PARP inhibitor. Indeed, DDR-defective NB cell lines were sensitive to PARP inhibitors. Thus, PARP inhibitors represent candidate NB therapeutics.

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Topoisomerase II alpha (TOP2A) has a crucial role in proper chromosome condensation and segregation. Here we report the interaction of TOP2A with ataxia telangiectasia mutated (ATM) and its phosphorylation in an ATM-dependent manner after DNA damage. In vitro kinase assay and site-directed mutagenesis studies revealed that serine 1512 is the target of phosphorylation through ATM. Serine 1512 to Alanine mutation of TOP2A showed increased stability of the protein, retaining TOP2A activity at least with regard to cell survival activity. Ataxia telangiectasiaderived cell lines showed high levels of TOP2A that were associated with hypersensitivity to the TOP2 inhibitor etoposide. These findings suggest that ATM-dependent TOP2A modification is required for proper regulation of TOP2 stability and subsequently of the sensitivity to TOP2 inhibitor. In a lymphoblastoid cell line derived from a patient who developed MLL rearrangement, positive infant leukemia, defective ATM expression, and increased TOP2A expression were shown. It was intriguing that hypersensitivity to TOP2 inhibitor and susceptibility to MLL gene rearrangement were shown by low-dose etoposide exposure in this cell line. Thus, our findings have clinically important implications for the pathogenesis of infantile acute leukemia as well as treatment-associated secondary leukemia following exposure to TOP2 inhibitors. (Cancer Sci 2013; 104: 178-184) A taxia telangiectasia (AT) is an autosomal recessive disorder characterized by a pleiotropic phenotype that includes progressive cerebellar degeneration, immunodeficiency, premature aging, genetic instability, and a high incidence of cancer. Heterozygous carriers also appear to be at increased risk of cancer.(1,2) Cells from AT homozygotes lack multiple cell cycle check points, and this leads to hypersensitivity to double-strand breaks in the DNA. (3,4) DNA topology is controlled and altered by DNA topoisomerases. Topoisomerases are ubiquitous enzymes that resolve topological problems, which arise during the various processes of DNA metabolism including transcription, recombination, replication, and chromosome partitioning during cell division. Topoisomerase I introduces a transient single-strand break into the DNA, passes an intact single strand of DNA through the broken strand, and re-ligates the break. Topoisomerase II (TOP2) makes transient double-strand breaks in one segment of DNA and passes an intact duplex through the broken DNA before resealing the breaks. Human cells express two isoforms of TOP2, topoisomerase II alpha (TOP2A) and topoisomerase II beta (TOP2B). TOP2A is expressed mainly during the S to G 2 ⁄ M phase of the cell cycle and is likely to play a major role in DNA catenation during mitosis. In contrast, TOP2B is expressed constantly throughout the cell cycle. The function of TOP2B is unknown, but the enzyme is speculated to be involved in the metabolism of DNA and ⁄ or RNA. Topoisomerase II alpha is highly phosphorylated, and its enzymatic activity has been postulated to be regulated by ph...

Cardiac dysfunction due to cardiotoxicity from anthracycline chemotherapy is a leading cause of morbidity and mortality in survivors of childhood cancer. The intraventricular pressure gradient (IVPG) of the left ventricle (LV) is the suction force of blood from the left atrium to the LV apex during early diastole and is a sensitive indicator of diastolic function. We assessed IVPG as a new indicator of the cardiac dysfunction in survivors of childhood cancer after anthracycline therapy. We performed a prospective echocardiographic study on 40 survivors of childhood cancer aged 6-26 years who received anthracycline therapy (group A) and 53 similar-age normal controls (group N).The subjects were divided into the younger groups, N1 and A1 (age <16 years); and older groups, N2 and A2 (age ≧16 years). IVPG was calculated using color M-mode Doppler imaging of the mitral inflow using Euler's equation. Total IVPG was divided into the basal and mid-to-apical IVPG to demonstrate more clearly the mechanisms of the LV diastolic suction force. The total anthracycline dose was 16.2-600.0 mg/m 2 (median 143.5 mg/m 2 ). Total IVPG significantly decreased in group A2 compared with that in group N2 (0.39 + 0.07 vs. 0.29 + 0.11 mmHg/cm; p = 0.010). The mid-to-apical IVPG significantly decreased in groups A1 and A2 compared with that in groups N1 and N2, respectively (N1 vs.