The online version of this article has a Supplementary Appendix. BackgroundEnhancer of zeste homolog 2 is a component of the Polycomb repressive complex 2 that mediates chromatin-based gene silencing through trimethylation of lysine 27 on histone H3. This complex plays vital roles in the regulation of development-specific gene expression. Design and MethodsIn this study, a comparative microarray analysis of gene expression in primary adult T-cell leukemia/lymphoma samples was performed, and the results were evaluated for their oncogenic and clinical significance. ResultsSignificantly higher levels of Enhancr of zeste homolog 2 and RING1 and YY1 binding protein transcripts with enhanced levels of trimethylation of lysine 27 on histone H3 were found in adult T-cell leukemia/lymphoma cells compared with those in normal CD4 + T cells. Furthermore, there was an inverse correlation between the expression level of Enhancer of zeste homolog 2 and that of miR-101 or miR-128a, suggesting that the altered expression of the latter miRNAs accounts for the overexpression of the former. Patients with high Enhancer of zeste homolog 2 or RING1 and YY1 binding protein transcripts had a significantly worse prognosis than those without it, indicating a possible role of these genes in the oncogenesis and progression of this disease. Indeed, adult T-cell leukemia/lymphoma cells were sensitive to a histone methylation inhibitor, 3-deazaneplanocin A. Furthermore, 3-deazaneplanocin A and histone deacetylase inhibitor panobinostat showed a synergistic effect in killing the cells ConclusionsThese findings reveal that adult T-cell leukemia/lymphoma cells have deregulated Polycomb repressive complex 2 with over-expressed Enhancer of zeste homolog 2, and that there is the possibility of a new therapeutic strategy targeting histone methylation in this disease.Key words: adult T-cell leukemia/lymphoma, human T-cell leukemia virus type-1, Enhancer of zeste homolog 2, H3K27me3. 2011;96(4):712-719. doi:10.3324/haematol.2010 This is an open-access paper. Citation: Sasaki D, Imaizumi Y, Hasegawa H, Osaka A, Tsukasaki K, Choi YL, Mano H, Marquez VE, Hayashi T, Yanagihara K, Moriwaki Y, Miyazaki Y, Kamihira S, and Yamada Y. Overexpression of enhancer of zeste homolog 2 with trimethylation of lysine 27 on histone H3 in adult T-cell leukemia/lymphoma as a target for epigenetic therapy HaematologicaOverexpression of enhancer of zeste homolog 2 with trimethylation of lysine 27 on histone H3 in adult T-cell leukemia/lymphoma as a target for epigenetic therapy

Adult T-cell leukemia/lymphoma (ATLL), an aggressive neoplasm etiologically associated with human T-lymphotropic virus type-1 (HTLV-1), is resistant to treatment. In this study, we examined the effects of a new inhibitor of deacetylase enzymes, LBH589, on ATLL cells. LBH589 effectively induced apoptosis in ATLL-related cell lines and primary ATLL cells and reduced the size of tumors inoculated in SCID mice. Analyses, including with a DNA microarray, revealed that neither death receptors nor p53 pathways contributed to the apoptosis. Instead, LBH589 activated an intrinsic pathway through the activation of caspase-2. Furthermore, small interfering RNA experiments targeting caspase-2, caspase-9, RAIDD, p53-induced protein with a death domain (PIDD) and RIPK1 (RIP) indicated that activation of RAIDD is crucial and an event initiating this pathway. In addition, LBH589 caused a marked decrease in levels of factors involved in ATLL cell proliferation and invasion such as CCR4, IL-2R and HTLV-1 HBZ-SI, a spliced form of the HTLV-1 basic zipper factor HBZ. In conclusion, we showed that LBH589 is a strong inducer of apoptosis in ATLL cells and uncovered a novel apoptotic pathway initiated by activation of RAIDD.

No abstract

PurposeThis study aimed to evaluate serum cytochrome c (cyto-c) levels as a novel role of tumor marker in patients with operable malignant tumors. Methods ConclusionSerum cyto-c is a potent tumor marker as a predictor for malignant potential in cancers.

: Falls cause injuries such as fractures, skin lacerations, bleeding, and head injury, and could result in more severe medical conditions in hospitalized patients. We retrospectively investigated the incidence and characteristics of falls among hospitalized patients in an acute care hospital from incident reports by hospital staff between January and June 2013. There were 154 falls in 135 patients, 2 of which resulted in fracture. The average age of patients who fell was 63.9 (range 0 to 91) years. Many falls occurred at the bedside (68.2% %). Approximately half of all falls were related to elimination (46.6% %). The most common time of discovery of falls was 2 : 00-2 : 59 AM (14/154 ; 9.1% %), followed by early in the morning when patients would actively move. Fall rates in our hospital were 1.39 falls per 1,000 patient days. The department of respiratory medicine and rheumatology had the highest fall rate (3.08 falls per 1,000 patient days), followed by the departments of neurosurgery and neurology (2.98 falls per 1,000 patient days). This study revealed the characteristics of falls in an acute care hospital, and suggests that their notification in the hospital might help reduce the incidence of falls in hospitalized patients. J. Med. Invest. 65 : 81-84, February, 2018