Azacitidine induces demethylation of p16INK4a and inhibits growth in adult T-cell leukemia/lymphoma

Uenogawa, Kumi; Hatta, Yoshihiro; Arima, Naomichi; Hayakawa, Satoshi; Sawada, Umihiko; Aizawa, Shin; Yamamoto, Tatsuo; Jin, Tao

doi:10.3892/ijmm.2011.756

Cited by 5 publications

(5 citation statements)

References 27 publications

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“…One of them suggests a more specific role of 5-azacytidine in the treatment of ATLL, as it shows a growth inhibition of leukemic cells, offering a potential new therapeutic approach to improve the poor outcomes associated with ATLL [52]. …”

Section: Discussionmentioning

confidence: 99%

Antiretroviral activity of 5-azacytidine during treatment of a HTLV-1 positive myelodysplastic syndrome with autoimmune manifestations

Diamantopoulos

Michael

Benopoulou

et al. 2012

Virol J

135

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Myelodysplastic syndromes (MDS) are often accompanied by autoimmune phenomena. The underlying mechanisms for these associations remain uncertain, although T cell activation seems to be important. Human T-lymphotropic virus (HTLV-1) has been detected in patients with myelodysplastic syndromes, mostly in regions of the world which are endemic for the virus, and where association of HTLV-1 with rheumatological manifestation is not rare. We present here the case of a 58 year old man who presented with cytopenias, leukocytoclastic vasculitis of the skin and glomerulopathy, and was diagnosed as MDS (refractory anemia with excess blasts - RAEB 1). The patient also tested positive for HTLV-1 by PCR. After 8 monthly cycles of 5-azacytidine he achieved a complete hematologic remission. Following treatment, a second PCR for HTLV-1 was carried out and found to be negative. This is the first report in the literature of a HTLV-1-positive MDS with severe autoimmune manifestations, which was treated with the hypomethylating factor 5-azacitidine, achieving cytogenetic remission with concomitant resolution of the autoimmune manifestations, as well as HTLV-1-PCR negativity. HTLV-1-PCR negativity may be due to either immune mediated clearance of the virus, or a potential antiretroviral effect of 5-azacytidine. 5-azacytidine is known for its antiretroviral effects, although there is no proof of its activity against HTLV-1 infection in vivo.

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Section: Discussionmentioning

confidence: 99%

Antiretroviral activity of 5-azacytidine during treatment of a HTLV-1 positive myelodysplastic syndrome with autoimmune manifestations

Diamantopoulos

Michael

Benopoulou

et al. 2012

Virol J

135

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“…Azacytidine is a cytotoxic cytosine analogue and DNA methyltransferase inhibitor with antineoplastic activity that can reverse the hypermethylation of tumour suppressor gene promoter regions [ 127 ]. For example, Kumi Uenogawa et al demonstrated that azacitidine induces the demethylation of p16 INK4a , which is implicated as a tumour suppressor gene, and inhibits cell growth in adult T-cell lymphoma [ 128 ]. Decitabine (5-aza-2′-deoxycytidine) is a more potent inhibitor of methyltransferases than 5-azacytidine and binds to DNA through a more direct metabolic activation pathway; in addition, it has been shown to have good antineoplastic activity in leukaemia and MDS [ 129 ].…”

Section: Dna Methylationmentioning

confidence: 99%

Epigenetic alterations and advancement of treatment in peripheral T-cell lymphoma

Zhang

2020

Clin Epigenet

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Peripheral T-cell lymphoma (PTCL) is a rare and heterogeneous group of clinically aggressive diseases associated with poor prognosis. Except for ALK + anaplastic large-cell lymphoma (ALCL), most peripheral T-cell lymphomas are highly malignant and have an aggressive disease course and poor clinical outcomes, with a poor remission rate and frequent relapse after first-line treatment. Aberrant epigenetic alterations play an important role in the pathogenesis and development of specific types of peripheral T-cell lymphoma, including the regulation of the expression of genes and signal transduction. The most common epigenetic alterations are DNA methylation and histone modification. Histone modification alters the level of gene expression by regulating the acetylation status of lysine residues on the promoter surrounding histones, often leading to the silencing of tumour suppressor genes or the overexpression of proto-oncogenes in lymphoma. DNA methylation refers to CpG islands, generally leading to tumour suppressor gene transcriptional silencing. Genetic studies have also shown that some recurrent mutations in genes involved in the epigenetic machinery, including TET2, IDH2-R172, DNMT3A, RHOA, CD28, IDH2, TET2, MLL2, KMT2A, KDM6A, CREBBP, and EP300, have been observed in cases of PTCL. The aberrant expression of miRNAs has also gradually become a diagnostic biomarker. These provide a reasonable molecular mechanism for epigenetic modifying drugs in the treatment of PTCL. As epigenetic drugs implicated in lymphoma have been continually reported in recent years, many new ideas for the diagnosis, treatment, and prognosis of PTCL originate from epigenetics in recent years. Novel epigenetic-targeted drugs have shown good tolerance and therapeutic effects in the treatment of peripheral T-cell lymphoma as monotherapy or combination therapy. NCCN Clinical Practice Guidelines also recommended epigenetic drugs for PTCL subtypes as second-line therapy. Epigenetic mechanisms provide new directions and therapeutic strategies for the research and treatment of peripheral T-cell lymphoma. Therefore, this paper mainly reviews the epigenetic changes in the pathogenesis of peripheral T-cell lymphoma and the advancement of epigenetic-targeted drugs in the treatment of peripheral T-cell lymphoma (PTCL).

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“…Methylation of 5′CpG islands in the p16 and RAR-β genes is associated with transcriptional gene silencing in many neoplasms, including solid tumors and leukemias [14]. Uenogawa et al [15] have reported that azacitidine induced demethylation of p16 in adult T-cell leukemia/lymphoma. The MSP analysis of p16 and RAR-β in SHI-1 cells aimed to assess the methylation status of the promoters in both genes.…”

Section: Discussionmentioning

confidence: 99%

Retinoic Acid Receptor-β Gene Reexpression and Biological Activity in SHI-1 Cells after Combined Treatment with 5-Aza-2′-Deoxycytidine and All-<b><i>Trans</i></b> Retinoic Acid

Xiang¹,

Wang²,

Qiu

et al. 2014

Acta Haematol

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Background: This study was conducted to determine the antineoplastic activities of 5-aza-2′-deoxycytidine (decitabine; DAC) and all-trans retinoic acid (ATRA), administered either alone or in combination, on in vitro cultured SHI-1 cells as well as their effects on the expression of the tumor suppressor gene p16^INK4a (p16) and the retinoic acid receptor (RAR)-β. Methods: Cellgrowth inhibition, differentiation and apoptosis were determined in SHI-1 cells treated with DAC and/or ATRA, and the combination index of the two compounds was calculated. Methylation of the p16 and RAR-β genes in SHI-1 cells was detected by methylation-specific polymerase chain reaction (PCR). Real-time quantitative reverse transcriptase PCR was used to detect mRNA expression of the p16 and RAR-β genes, and Western blot analysis was performed for protein expression. Results: The drug combination had a synergistic effect on growth inhibition, differentiation and apoptosis of SHI-1 cells, and the effects of DAC and ATRA weredependent on time. DAC, either alone or in combination with ATRA, induced demethylation of the genes p16 and RAR-β, whereas ATRA alone had no effect on methylation. The RAR-β gene was reexpressed following DAC-ATRA combination treatment, and both agents had no effect on p16 expression. Conclusion: The results revealed that DAC used in combination with ATRA has significant clinical potential in the treatment of acute monocytic leukemia. © 2014 S. Karger AG, Basel

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Azacitidine induces demethylation of p16INK4a and inhibits growth in adult T-cell leukemia/lymphoma

Cited by 5 publications

References 27 publications

Antiretroviral activity of 5-azacytidine during treatment of a HTLV-1 positive myelodysplastic syndrome with autoimmune manifestations

Antiretroviral activity of 5-azacytidine during treatment of a HTLV-1 positive myelodysplastic syndrome with autoimmune manifestations

Epigenetic alterations and advancement of treatment in peripheral T-cell lymphoma

Retinoic Acid Receptor-β Gene Reexpression and Biological Activity in SHI-1 Cells after Combined Treatment with 5-Aza-2′-Deoxycytidine and All-<b><i>Trans</i></b> Retinoic Acid

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