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DNA demethylating agents and EZH2 inhibitors for Adult T cell leukemia

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE189604 | GEO | 2023/05/03

REPOSITORIES: GEO

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DNA demethylating agents and EZH2 inhibitors for Adult T cell leukemia [Affymetrix]

Project description:Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature CD4+ T-cells caused by human T-cell lymphotropic virus type 1 (HTLV-1). Recently, it has been noted that some epigenome abnormalities including DNA methylation and tri-methylation at histone H3Lys27 (H3K27me3) contribute to malignant transformation of ATL. Hence, we investigate the combined effect of DNA demethylating agents and enhancer of zeste homolog 2 (EZH2), which catalyze H3K27me3, inhibitors in ATL. Gene expression microarray analyses revealed that the combination changes gene expressions stronger than the single treatment.

2023-05-03 | GSE189603 | GEO

DNA demethylating agents and EZH2 inhibitors for Adult T cell leukemia [Illumina]

Project description:Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature CD4+ T-cells caused by human T-cell lymphotropic virus type 1 (HTLV-1). Recently, it has been noted that some epigenome abnormalities including DNA methylation and tri-methylation at histone H3Lys27 (H3K27me3) contribute to malignant transformation of ATL. Hence, we investigate the combined effect of DNA demethylating agents and enhancer of zeste homolog 2 (EZH2), which catalyze H3K27me3, inhibitors in ATL. Methylaome analyse revealed that OR21 and the combination changes DNA methylation.

2023-05-03 | GSE189602 | GEO

Adult T-cell leukemia-lymphoma acquires resistance to DNA demethylating agents through dysregulation of enzymes involved in pyrimidine metabolism.

Project description:Adult T-cell leukemia-lymphoma (ATL) is an aggressive neoplasm derived from T-cells transformed by human T-cell lymphotropic virus-1 (HTLV-1). Recently, we reported that regional DNA hypermethylation in HTLV-1-infected T-cells reflects the disease status of ATL and the anti-ATL effects of DNA demethylating agents, including azacitidine (AZA), decitabine (DAC) and a new DAC prodrug, OR-2100 (OR21), which we developed. Here, to better understand the mechanisms underlying drug resistance, we generated AZA-, DAC- and OR21-resistant (AZA-R, DAC-R and OR21-R, respectively) cells from the ATL cell line TL-Om1 and the HTLV-1-infected cell line MT-2 via long-term drug exposure. The efficacy of OR21 was almost the same as that of DAC, indicating that the pharmacodynamics of OR21 were due to release of DAC from OR21. Resistant cells did not show cellular responses observed in parental cells induced by treatment with drugs, including growth suppression, depletion of DNA methyltransferase DNMT1 and DNA hypomethylation. We also found that reduced expression of deoxycytidine kinase (DCK) correlated with lower susceptibility to DAC/OR21 and that reduced expression of uridine cytidine kinase2 (UCK2) correlated with reduced susceptibility to AZA. DCK and UCK2 catalyze phosphorylation of DAC and AZA, respectively; reconstitution of expression reversed the resistant phenotypes. A large homozygous deletion in DCK and a homozygous splice donor site mutation in UCK2 were identified in DAC-R TL-Om1 and AZA-R TL-Om1, respectively. Both genomic mutations might lead to loss of protein expression. Thus, inactivation of UCK2 and DCK might be a putative cause of phenotypes that are resistant to AZA and DAC/OR21, respectively.

| S-EPMC9303000 | biostudies-literature

Mutation of bphP/bphR Decreases the Resistance of D. radiodurans to DNA-damaging Agents

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2014-07-07 | E-GEOD-59139 | biostudies-arrayexpress

Enhancing the Cytotoxic Effects of PARP Inhibitors with DNA Demethylating Agents - A Potential Therapy for Cancer.

Project description:Poly (ADP-ribose) polymerase inhibitors (PARPis) are clinically effective predominantly for BRCA-mutant tumors. We introduce a mechanism-based strategy to enhance PARPi efficacy based on DNA damage-related binding between DNA methyltransferases (DNMTs) and PARP1. In acute myeloid leukemia (AML) and breast cancer cells, DNMT inhibitors (DNMTis) alone covalently bind DNMTs into DNA and increase PARP1 tightly bound into chromatin. Low doses of DNMTis plus PARPis, versus each drug alone, increase PARPi efficacy, increasing amplitude and retention of PARP1 directly at laser-induced DNA damage sites. This correlates with increased DNA damage, synergistic tumor cytotoxicity, blunting of self-renewal, and strong anti-tumor responses, in vivo in unfavorable AML subtypes and BRCA wild-type breast cancer cells. Our combinatorial approach introduces a strategy to enhance efficacy of PARPis in treating cancer.

| S-EPMC5201166 | biostudies-literature

Analysis of PRC2 isogenic human MPNST cells with or without DNA demethylating therapy

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-08-17 | GSE179587 | GEO

Tumor suppressor role of Ezh2 in an NRASQ61K driven model of Early T-cell Precursor Acute Lymphoblastic Leukemia

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2016-01-07 | E-GEOD-76603 | biostudies-arrayexpress

A DNA Hypomethylation Signature Predicts Novel Anti-Tumor Activity of LSD1 Inhibitors in SCLC

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2015-07-14 | E-GEOD-66298 | biostudies-arrayexpress

Catalytic subunits switch drives resistance to EZH2 inhibitors in ARID1A-mutated cells

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-02-10 | GSE110450 | GEO

DNMT and EZH2 inhibitors synergize for gene activation in hepatocellular carcinoma cells.

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-10-19 | GSE202561 | GEO

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