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Abstract: We performed methylation specific PCR analysis on the RIZ1 promoter in MDS and AML. Methylation was detected in 17 of 34 MDS (50%) and 22 of 72 AML (31%) (p =0.053). Methylation was detected in eleven of 17 secondary AML from MDS (65%), and eleven of 55 de novo AML (20%) (p =0.0005). Bisulfite sequence revealed methylation at many CpG sites in the promoter. Decreased RIZ1 expression was accompanied by methylation in six of nine samples examined, while it was also observed in seven of 13 without methylation. Treatment of AML cells, that have RIZ1 methylation, with 5-Aza-dC, induced growth suppression with RIZ1 restoration. Our results suggest that the RIZ1 gene is inactivated in MDS and AML in part by methylation, whereas another mechanism should be involved in others. [Copyright &y& Elsevier]

Abstract: The DNA topoisomerase IIα (Topo IIα) is known as a target enzyme for many chemotherapeutic agents. We investigated the Topo IIα mRNA expression by real-time RT-PCR in 37 paired samples at diagnosis and at relapse of acute leukemic patients in relation to drug sensitivity and clinical outcome. The Topo IIα levels in leukemic blasts at relapse were significantly higher than that at diagnosis, especially in ALL. The increase in the Topo IIα level at relapse was significant in cases which could not achieve a second remission, but not significant in cases which achieved a second remission. These results suggest that the change of Topo IIα expression in leukemic blasts at relapse may predict therapeutic responsiveness. [Copyright &y& Elsevier]

Abstract: Activation of the activator protein 1 (AP-1) plays a critical role in oncogenesis by human T-cell leukemia virus type 1 (HTLV-1), the etiologic agent of adult T-cell leukemia (ATL), and is required for maintenance of the malignant phenotype. Curcumin (diferuloylmethane), the major pigment of the spice turmeric, has anti-tumor activity; however, the effect of curcumin against ATL has not been elucidated. In this study, we examined the effects of curcumin on AP-1 activity in HTLV-1-infected T-cell lines. Curcumin suppressed the constitutive AP-1 DNA-binding and transcriptional activity in HTLV-1-infected T-cell line. Curcumin also inhibited HTLV-1 Tax-induced AP-1 transcriptional activity. JunD was detectable as a major component of the AP-1–DNA complex in HTLV-1-infected T-cell lines using the supershift assay. The expression of JunD was suppressed by curcumin treatment. Curcumin inhibited the growth of HTLV-1-infected T-cell lines by inducing cell cycle arrest followed by apoptosis. Our results suggest that suppression of the constitutively active AP-1 by curcumin is due to, at least in-part, reducing the expression of JunD by curcumin. Inhibition of AP-1 activity by curcumin may be one of the mechanisms responsible for the anti-ATL effect of curcumin. We propose that curcumin is a potentially promising compound for the treatment of ATL. [Copyright &y& Elsevier]

We investigated methylation status of the adenomatous polyposis coli (APC) gene in adult T-cell leukemia/lymphoma (ATL). APC methylation was found in 15 of 31 (48%) primary samples, and 2 of 4 (50%) ATL cell lines. Methylation of the APC gene occurred more frequently in acute ATL (12/21) (57%) than chronic ATL (1/8) (13%) (P = 0.03). APC was not expressed in the APC-methylated ATL cell line ST1. Demethylation with 5-azacytidine treatment restored APC expression in the ST1 cell line. Our data show that hypermethylation of the APC gene is involved in the pathogenesis of ATL. [Copyright &y& Elsevier]

• Among 26 genes examined, expression of 8 genes was reduced in patients with del(20q). • Expression of 3 genes was reduced in patients without del(20q). • Reduced BCAS4 expression could be a prognostic marker for MDS. Deletion of the long arm of chromosome 20 (del(20q)) is observed in 5–10% of patients with myelodysplastic syndromes (MDS). We examined the expression of 28 genes within the common deleted region (CDR) of del(20q), which we previously determined by a CGH array using clinical samples, in 48 MDS patients with (n = 28) or without (n = 20) chromosome 20 abnormalities and control subjects (n = 10). The expression level of 8 of 28 genes was significantly reduced in MDS patients with chromosome 20 abnormalities compared to that of control subjects. In addition, the expression of BCAS4 , ADA , and YWHAB genes was significantly reduced in MDS patients without chromosome 20 abnormalities, which suggests that these three genes were commonly involved in the molecular pathogenesis of MDS. To evaluate the clinical significance, we analyzed the impact of the expression level of each gene on overall survival (OS). According to the Cox proportional hazard model, multivariate analysis indicated that reduced BCAS4 expression was associated with inferior OS, but the difference was not significant (HR, 3.77; 95% CI, 0.995-17.17; P = 0.0509). Functional analyses are needed to understand the biological significance of reduced expression of these genes in the pathogenesis of MDS. [ABSTRACT FROM AUTHOR]