Impact of p53 aberration on the progression of Adult T-cell Leukemia/Lymphoma

Tawara, Masayuki; Hogerzeil, Simon J.; Yamada, Yasuaki; Takasaki, Yozo; Soda, Hiroshi; Hasegawa, Hiroo; Murata, Ken T.; Ikeda, Shu‐ichi; Imaizumi, Yoshitaka; Sugahara, Kazuyuki; Tsuruda, Kazuto; Tsukasaki, Kunihiro; Tomonaga, Masao; Hirakata, Yoichi; Kamihira, Shimeru

doi:10.1016/j.canlet.2005.03.039

Cited by 53 publications

(36 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…13 Inactivation of tumor suppressor genes is one of the key events in development and progression, and there is a strong accumulation of p14ARF/p15INK4B/p16INK4A gene deletion/methylation or p53 gene mutations in aggressive subtypes (>60%). [14][15][16][17][18][19][20] In the present study, for further investigation of the oncogenesis of ATL, we performed a comparative microarray analysis of gene expression in primary ATL samples. ATL cells expressed significantly higher levels of EZH2 and RYBP (RING1 and YY1 binding protein) transcripts than CD4 + T cells from healthy volunteers.…”

Section: Introductionmentioning

confidence: 99%

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

Sasaki¹,

Imaizumi²,

Hasegawa³

et al. 2011

Haematologica

View full text Add to dashboard Cite

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

show abstract

Section: Introductionmentioning

confidence: 99%

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

Sasaki¹,

Imaizumi²,

Hasegawa³

et al. 2011

Haematologica

View full text Add to dashboard Cite

show abstract

“…23,24 As mutated p53 proteins have been found in less than one-fourth of ATL cases and Tax expression is frequently lost in primary ATL cells, the activation of p53 by therapeutic drugs may become a promising approach to ATL therapy. 13,25 In this study we analyze the potential therapeutic utility of Nutlin-3a in a number of ATL-related cell lines. Our experiments also provide new insights into the mechanism of cellular senescence and the possibility of expanding Nutlin-3a-based cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

Activation of p53 by Nutlin-3a, an antagonist of MDM2, induces apoptosis and cellular senescence in adult T-cell leukemia cells

et al. 2009

View full text Add to dashboard Cite

It has been reported that the induction of cellular senescence through p53 activation is an effective strategy in tumor regression. Unfortunately, however, tumors including adult T-cell leukemia/lymphoma (ATL) have disadvantages such as p53 mutations and a lack of p16INK4a and/or p14 ARF. In this study we characterized Nutlin-3a-induced cell death in 16 leukemia/ lymphoma cell lines. Eight cell lines, including six ATL-related cell lines, had wild-type p53 and Nutlin-3a-activated p53, and the cell lines underwent apoptosis or cell-cycle arrest, whereas eight cell lines with mutated p53 were resistant. Interestingly, senescence-associated-b-galactosidase (SA-b-gal) staining revealed that only ATL-related cell lines with wild-type p53 showed cellular senescence, although they lack both p16 . Furthermore, knockdown of Tp53-induced glycolysis and apoptosis regulator (TIGAR), a novel target gene of p53, by small interfering RNA(siRNA) indicated its important role in the induction of cellular senescence. As many patients with ATL carry wild-type p53, our study suggests that p53 activation by Nutlin-3a is a promising strategy in ATL. We also found synergism with a combination of Nutlin-3a and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), suggesting the application of Nutlin-3a-based therapy to be broader than expected.

show abstract

“…The pathogenesis of HTLV-1 has been investigated intensively in terms of the viral regulatory protein HTLV-1 Tax or Rex, which is supposed to play key roles in the HTLV-1 leukemogenesis/ lymphomagenesis, as well as the recently discovered HTLV-1 basic leucine zipper factor. 6 -8 We and others have reported the progression mechanism of ATLL from various genetic aspects, including specific chromosome abnormalities, 9 -14 changes of characteristic HTLV-1 Tax and Rex protein expression pattern, 14 and aberrant expression of the SHP1, 10,15 p53, 16,17 MEL1S, 17 DRS, 18 and ASY/Nogo genes, although, the detailed mechanism triggering the onset and progression of ATLL remains to be elucidated. On the other hand, epigenetic aberration processes have been recognized to play another important role in carcinogenesis.…”

mentioning

confidence: 99%

Multi-Step Aberrant CpG Island Hyper-Methylation Is Associated with the Progression of Adult T–Cell Leukemia/Lymphoma

Sato

Oka

Shinnou

et al. 2010

The American Journal of Pathology

View full text Add to dashboard Cite

Aberrant CpG island methylation contributes to the pathogenesis of various malignancies. However, little is known about the association of epigenetic abnormalities with multistep tumorigenic events in adult T cell leukemia/lymphoma (ATLL). To determine whether epigenetic abnormalities induce the progression of ATLL , we analyzed the methylation profiles of the SHP1 , p15 , p16 , p73 , HCAD, DAPK , hMLH-1, and MGMT genes by methylation specific PCR assay in 65 cases with ATLL patients. The number of CpG island methylated genes increased with disease progression and aberrant hypermethylation in specific genes was detected even in HTLV-1 carriers and correlated with progression to ATLL. The CpG island methylator phenotype (CIMP) was observed most frequently in lymphoma type ATLL and was also closely associated with the progression and crisis of ATLL. The high number of methylated genes and increase of CIMP incidence were shown to be unfavorable prognostic factors and correlated with a shorter overall survival by Kaplan-Meyer analysis. The present findings strongly suggest that the multistep accumulation of aberrant CpG methylation in specific target genes and the presence of CIMP are deeply involved in the crisis , progression , and prognosis of ATLL , as well as indicate the value of CpG methylation and CIMP for new diagnostic and prognostic biomarkers.

show abstract

Impact of p53 aberration on the progression of Adult T-cell Leukemia/Lymphoma

Cited by 53 publications

References 20 publications

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

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

Activation of p53 by Nutlin-3a, an antagonist of MDM2, induces apoptosis and cellular senescence in adult T-cell leukemia cells

Multi-Step Aberrant CpG Island Hyper-Methylation Is Associated with the Progression of Adult T–Cell Leukemia/Lymphoma

Contact Info

Product

Resources

About