A genomic analysis of adult T-cell leukemia

Choi, Young Lim; Tsukasaki, K; O'Neill, Michael C.; Yamada, Yasuaki; Onimaru, Yasuyuki; Matsumoto, Kunio; Ohashi, Jun; Yamashita, Yuichi; Tsutsumi, Sadami; Kaneda, Ruri; Takada, Shuji; Aburatani, Hiroyuki; Kamihira, Shimeru; Nakamura, Toshikazu; Tomonaga, Masao; Mano, Hiroyuki

doi:10.1038/sj.onc.1209898

Cited by 72 publications

(50 citation statements)

References 36 publications

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“…SIRT4 mRNA levels are reduced in several human cancers (13,26,45,71,170), and reduced SIRT4 mRNA levels correlate with inferior survival in patients with lung tumors (71). Recent studies confirmed that SIRT4 indeed acts as a tumor suppressor, by repressing glutamine metabolism and promoting genomic stability (30,69,71).…”

Section: Sirt4 Acts As a Tumor Suppressor Via Repression Of Glutaminementioning

confidence: 99%

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

Kumar

Lombard²

2015

Antioxidants & Redox Signaling

127

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Significance: Maintenance of metabolic homeostasis is critical for cellular and organismal health. Proper regulation of mitochondrial functions represents a crucial element of overall metabolic homeostasis. Mitochondrial sirtuins (SIRT3, SIRT4, and SIRT5) play pivotal roles in promoting this homeostasis by regulating numerous aspects of mitochondrial metabolism in response to environmental stressors. Recent Advances: New work has illuminated multiple links between mitochondrial sirtuins and cancer. SIRT5 has been shown to regulate the recently described post-translational modifications succinyl-lysine, malonyllysine, and glutaryl-lysine. An understanding of these modifications is still in its infancy. Enumeration of SIRT3 and SIRT5 targets via advanced proteomic techniques promises to dramatically enhance insight into functions of these proteins. Critical Issues: In this review, we highlight the roles of mitochondrial sirtuins and their targets in cellular and organismal metabolic homeostasis. Furthermore, we discuss emerging roles for mitochondrial sirtuins in suppressing and/or promoting tumorigenesis, depending on the cellular and molecular context. Future Directions: Currently, hundreds of potential SIRT3 and SIRT5 molecular targets have been identified in proteomic experiments. Future studies will need to validate the major targets of these enzymes, and elucidate how acetylation and/or acylation modulate their functionality. A great deal of interest exists in targeting sirtuins pharmacologically; this endeavor will require development of sirtuin-specific modulators (activators and inhibitors) as potential treatments for cancer and metabolic disease. Antioxid.

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Section: Sirt4 Acts As a Tumor Suppressor Via Repression Of Glutaminementioning

confidence: 99%

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

Kumar

Lombard²

2015

Antioxidants & Redox Signaling

127

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“…[15][16][17][18] Over-expression of MET has also been detected in cell lines established from Asian-prevalent head and neck cancer, nasopharyngeal cancer, pediatric tumors including osteogenic sarcoma and neuroblastoma, and hematopoietic malignancies including multiple myeloma and adult T-cell leukemia. [19][20][21][22][23] Constitutive MET activation due to MET amplification and/or MET mutation has been found to be a driver of proliferation and survival. MET expression correlates with an aggressive phenotype and poor prognosis.…”

Section: Met and Cancermentioning

confidence: 99%

Receptor Tyrosine Kinases and Targeted Cancer Therapeutics

Takeuchi

Ito

2011

Biological & Pharmaceutical Bulletin

142

113

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The majority of growth factor receptors are composed of extracellular, transmembrane, and cytoplasmic tyrosine kinase (TK) domains. Receptor tyrosine kinase (RTK) activation regulates many key processes including cell growth and survival. However, dysregulation of RTK has been found in a wide range of cancers, and it has been shown to correlate with the development and progression of numerous cancers. Therefore, RTK has become an attractive therapeutic target. One way to effectively block signaling from RTK is inhibition of its catalytic activity with small-molecule inhibitors. Low-molecular-weight TK inhibitors (TKIs), such as imatinib, targeting tumors with mutant c-Kit, and gefitinib, targeting non-small cell lung cancer with mutant epidermal growth factor receptor (EGFR), have received marketing approval in Japan. MET, fibroblast growth factor receptor (FGFR), and insulin-like growth factor-I receptor (IGF-IR) are frequently genetically altered in advanced cancers. TKIs of these receptors have not yet appeared on the market, but many anticancer drug candidates are currently undergoing clinical trials. Most of these TKIs were designed to compete with ATP at the ATP-binding site within the TK domain. This review will focus on small-molecule TKIs targeting MET, FGFR, and IGF-IR and discuss the merits and demerits of two types of agents, i.e., those with only one or a few targets and those directed at multiple targets. Targeting agents specifically inhibiting the target kinase were previously searched for based on the hypothesis that a narrow target window might reduce unexpected side effects, but agents with multiple targets have been recently developed to overcome tumors resistant against a single-targeting agent.

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“…For enrichment of ATL cells, CD4 + cells were purified from the PBMCs by the magnetic bead method (CD4 MicroBeads, Miltenyi Biotec, Auburn, CA, USA) as described elsewhere. 25 Besides these samples for microarray analysis, we prepared another set of samples for quantitative real-time RT-PCR (qRT-PCR) and Western blotting (25 ATL patients, 13 HTLV-1 carriers, and 12 healthy adults) to confirm the results of microarray analysis. We also used formalin-fixed, paraffin-embedded lymph nodes from 7 patients with lymphoma-type ATL and 5 patients with follicular lymphoma for immunohistochemical analysis.…”

Section: Sample Preparationmentioning

confidence: 99%

“…25,27 The mean expression intensity of the internal positive control probe sets (http://www.affymetrix.com/support/technical/mask_files.affx) was set to 500 units in each hybridization, and the fluorescence intensity of each test gene was normalized accordingly. All HGU133A & B microarray data are available from the Gene Expression Omnibus website (http://www.ncbi.nlm.nih.gov/geo) under the accession number GSE1466.…”

Section: Dna Microarray Analysismentioning

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

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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

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A genomic analysis of adult T-cell leukemia

Cited by 72 publications

References 36 publications

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

Receptor Tyrosine Kinases and Targeted Cancer Therapeutics

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

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