Dataset Information

Redox-dependent protein S-glutathionylation governs azacitidine sensitivity and resistance in AML

ABSTRACT: Hypomethylation therapy significantly prolongs survival of patients with high-risk myelodysplastic syndrome progressing to acute myeloid leukaemia, yet most patients develop resistance. In this work we identified redox-regulated mechanisms of hypomethylation therapy and revealed that in resistant cells, hypomethylation therapy is failing to induce oxidative modifications of proteins. Modulation of redox homeostasis by targeting glutathione metabolism induces protein oxidation in resistant cells and overcomes chemoresistance.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Myeloblast, Cell Culture, Myeloid Cell

DISEASE(S): Acute Leukemia

SUBMITTER: Kristyna Gloc Pimkova

LAB HEAD: Kristyna Gloc

PROVIDER: PXD056452 | Pride | 2026-01-12

REPOSITORIES: Pride

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Redox-dependent protein S-glutathionylation governs azacitidine sensitivity and resistance in AML.

Nemes Dušan D Myšáková Michaela M Minařík Lubomír L Jonášová Anna A Stopka Tomáš T Pimková Kristýna Gloc KG

Redox biology 20251204

Disruption of redox metabolism is a hallmark of drug-resistant cancer cells, representing a major obstacle to the effective treatment of acute myeloid leukemia (AML). While recent studies have highlighted the importance of redox balance in AML therapy, the specific contribution of protein redox signaling to resistance remains poorly understood. Defining these mechanisms could uncover therapeutic vulnerabilities of resistant AML cells and guide the development of novel combination strategies. Her ...[more]

PMID: 41389768

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Project description:The epigenetic regulation of transcription factor genes is critical for T cell lineage specification. A specific methylation pattern within a conserved region of the lineage specifying transcription factor gene FOXP3, the Treg-specific demethylated region (TSDR), is restricted to regulatory T (Treg) cells and required for stable expression of FOXP3 and suppressive function. We analyzed the impact of hypomethylating agents 5-Aza-2`-deoxycytidine and Epigallocatechin-3-gallate (EGCG) on human CD4+CD25- T for generating Treg cell specific DNA methylation pattern within FOXP3-TSDR and inducing functional Treg cells. Gene expression, including lineage specifying transcription factors of the major T cell lineages and their leading cytokines, functional properties and global transcriptome changes were analyzed. 5-Aza-2`-deoxycytidine induced FOXP3-TSDR methylation and expression of Treg cell specific genes FOXP3 and LRRC32. Proliferation of 5-Aza-2Â´deoxycytidine treated cells was reduced, but they did not show suppressive function. Hypomethylation was not restricted to FOXP3-TSDR and expression of master transcription factors and leading cytokines of Th1 and Th17 cells were induced. EGCG induced global DNA hypomethylation to a lower degree than 5-Aza-2Â´deoxycitidine, but no relevant hypomethylation within FOXP3-TSDR or expression of Treg cell specific genes. Both DNMT inhibitors did not induce full functional human Treg cells. Although 5-Aza-2`-deoxycytidine treated cells phenotypically appeared to be Treg cells, they did not suppress proliferation of responder cells, which is an essential capability to be used in Treg cell transfer therapy. In this study we analyze the potency of the two hypomethylating agents 5-Aza-2`-deoxycytidine (5-Aza-dC) and Epigallocatechin-3-gallate (EGCG) for in vitro induction of functional Treg cell cells through generation of a specific methylation pattern within FOXP3-TSDR. We analyzed the expression of Treg cell specific genes and for their functional properties from CD4+CD25- T cells. 5-Aza-dC is a derivative of 5-Azacytidine. Both substances are inhibitors of DNA methyltransferases (DNMTs) and used for therapy of patients with myelodysplastic syndrome and acute myeloid leukaemia. In these patients, 5-Azacytidine has been reported to augment regulatory T cell expansion in blood. EGCG is the most abundant catechin of green tea and has been reported to have cardio protective, anti-cancer, anti-infective properties and protective effects on autoimmune diseases. EGCG has also been described as a potent inhibitor of DNMTs and to induce Foxp3 in Jurkat T cell line.

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	iodoTMTquant_Sequest.pdResult	Other