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A new hypomethylating agent, OR-2100, resists degradation by cytidine deaminase, leading to favorable oral absorbability and anti-leukemia effects

ABSTRACT: DNA methyltransferase inhibitors have improved the prognosis of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). However, these agents must be administered intravenously or subcutaneously because they are degraded easily by cytidine deaminase (CDA). OR2100 (OR21), an oligonucleotide comprising decitabine nucleoside 5'-O-trisilylate, resists degradation by CDA. Direct duodenal administration led to high plasma concentrations of OR21 in a cynomolgus monkey model. Transcriptome and methylome analysis of MDS and AML cell lines revealed that OR21 enriched expression of genes associated with tumour suppression, cell differentiation, and immune system processes via alteration of regional promoter methylation. Conversely, immune system process pathways were downregulated in azacytidine-resistant AML cells, indicating that these pathways play a pivotal role in the action of hypomethylating agents. Both in vivo and in vitro, OR21 showed anti-leukaemia effects against MDS and AML cells (including AZA-resistant), and a better safety profile than decitabine. These results suggest that OR21 is a candidate drug for a phase 1 study as an alternative to DAC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE148314 | GEO | 2020/04/09

REPOSITORIES: GEO

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A new hypomethylating agent, OR-2100, resists degradation by cytidine deaminase, leading to favourable oral absorbability and ant-leukaemia effects

Project description:DNA methyltransferase inhibitors have improved the prognosis of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). However, these agents must be administered intravenously or subcutaneously because they are degraded easily by cytidine deaminase (CDA). OR2100 (OR21), an oligonucleotide comprising decitabine nucleoside 5'-O-trisilylate, resists degradation by CDA. Direct duodenal administration led to high plasma concentrations of OR21 in a cynomolgus monkey model. Microarray analysis of MDS and AML cell lines revealed that OR21 enriched expression of genes associated with tumour suppression, cell differentiation, and immune system processes. Conversely, immune system process pathways were downregulated in azacytidine-resistant AML cells, indicating that these pathways play a pivotal role in the action of hypomethylating agents. Both in vivo and in vitro, OR21 showed anti-leukaemia effects against MDS and AML cells, and a better safety profile than decitabine. These results suggest that OR21 is a candidate drug for a phase 1 study as an alternative to DAC.

2020-06-30 | GSE141677 | GEO

Genome-Wide CRISPR-Cas9 Screening Identifies a Synergy between Hypomethylating Agents and SUMOylation Blockade in Myelodysplastic Syndromes and Acute Myeloid Leukemia

Project description:Hypomethylating agents (HMAs) are frontline therapies effective at altering the natural course of Myelodysplastic Neoplasms (MDS). However, acquired resistance and treatment failure are hallmarks of HMA therapy. Developing effective and rational HMA-focused combinatorial therapies is challenging as the underlying mechanisms driving HMA efficacy are complex. To address this clinical need, we performed a genome-wide CRISPR-Cas9 screen in a human MDS-derived cell line, MDS-L, and characterized TOPORS as a highly ranked target that synergizes with HMAs to reduce leukemic burden and improve survival in xenograft models. We demonstrated that the depletion of TOPORS mediates sensitivity to HMAs by predisposing leukemic blasts to an impaired DNA damage response (DDR) accompanied by an accumulation of SUMOylated DNMT1 in HMA-treated TOPORS-depleted cells. Importantly, the combination of HMAs with targeting of TOPORS did not functionally impair healthy hematopoiesis. While inhibitors of TOPORS are currently unavailable, we show that inhibition of SUMOylation (upstream of TOPORS functions) with TAK-981 partially phenocopies HMA-sensitivity and DDR impairment. Overall, our data suggest that the combination of HMAs with the inhibition of SUMOylation demonstrates a favourable therapeutic index and represents a rational framework towards the treatment of High-Risk MDS (HR-MDS) or Acute Myeloid Leukemia (AML).

2024-07-25 | PXD050539 | Pride

Genomics of decitabine responses

Project description:Global DNA methylation was analyzed in total bone marrow cells of AML/MDS patients undergoing decitabine treatment.

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Gene expression profiling in primary AML cells treated with decitabine and cytarabine

Project description:Acute myeloid leukemia (AML), and other myeloid malignancies, are frequently treated with hypomethylating agents like decitabine. Alterations in the epigenome, induced by decitabine, are likely to result in gene expression changes. The effects of decitabine have not been systemically studied using primary AML samples. We cultured 18 different primary AML samples for 7 days, the last 3 days of which included 100 nM decitabine (DAC) or 100 nm cytarabine (AraC). We hypothesized that decitabine treatment would result in detectable and consistent gene expression changes. For comparison, we also analyzed mRNA from cells treated with DMSO control (mock) and mRNA from uncultured cells taken at the time of diagnosis.

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CpG methylation patterns and decitabine treatment response in acute myeloid leukemia cells and normal hematopoietic precursors

Project description:The DNA hypomethylating drug decitabine maintains normal hematopoietic stem and progenitor cell (HSPC) self-renewal but induces terminal differentiation in acute myeloid leukemia (AML) cells. To better understand the basis for this contrasting treatment effect, the baseline expression of key lineage-specifying transcription factor (TF) (eg., CEBPa) and key late differentiation TF (CEBPe), was examined in normal, myelodysplastic (MDS) and AML primary cells and cell lines. To appreciate the role of differentiation in hypomethylation of some CpG by decitabine treatment but not others, promoter CpGs, analyzed by microarray and mass spectrometry, were categorized by the direction of methylation change during normal myeloid differentiation. In MDS/AML cells, high expression of CEBPa, relatively low expression of CEBPe (a gene target of CEBPa), hypermethylation of CEBPe promoter CpG, and the methylation pattern at differentiation sensitive promoter CpGs analyzed by microarray, suggested lineage-commitment and aberrant epigenetic repression of late differentiation genes. DNA hypomethylation in response to decitabine was greatest at CpGs that are hypomethylated during normal myeloid differentiation. In contrast, normal HSPC treated with decitabine retained immature morphology, and methylation significantly decreased at CpG that are hypermethylated during myeloid differentiation. Partial differentiation at baseline, and repression of key late differentiation genes by epigenetic means, likely plays a role in methylation and phenotype responses of AML cells treated with decitabine. Bisulphite converted DNA from the 208 samples were hybridised to the Illumina Cancel Panel 1 GPL9183 methylation assay

2011-07-01 | E-GEOD-29047 | biostudies-arrayexpress

Gene expression profiling in primary AML cells treated with decitabine and cytarabine

2012-12-18 | GSE40442 | GEO

Gene expression profiling of myelodysplastic CD34+ hematopoietic stem cells treated in vitro with decitabine

Project description:Epigenetic mechanisms contribute to deregulated gene expression of hematopoietic progenitors in Myelodysplastic Syndromes (MDS). Hypomethylating agents are able to improve peripheral cytopenias in MDS patients. To identify critical gene expression changes induced by hypomethylating agents, we analyzed gene expression profiling (GEP) of myelodysplastic and normal CD34+ hematopoietic stem cells treated in vitro with or without decitabine. Four MDS and two untreated early stage Hodgkin’s lymphomas were analyzed for GEP. Mock treated CD34+ stem cells segregate according to diagnosis and karyotype. After decitabine treatment, gene expression changes were more consistent on MDS CD34+ cells with abnormal kayotype. Comparing decitabine-induced genes with those found down-regulated in mock-treated MDS cells, we identified a list of candidate tumor suppressor genes in MDS. By real-time RT-PCR we confirmed expression changes for three selected genes CD9, CXCR4 and GATA2 in 12 MDS patients and 4 controls. CD9 was widely repressed in most MDS CD34+ cell samples, although similar levels of methylation were found in both normal and MDS total bone marrows. CXCR4 promoter methylation was absent in total bone marrows from 36 MDS patients. In conclusion, changes in gene expression changes induced by hypomethylating treatment are more pronounced in CD34+ cells from abnormal karyotype.

2009-12-23 | GSE19610 | GEO

Analysis of genome-wide methylation and gene expression induced by decitabine treatment in HL60 leukemia cell line

Project description:Epigenetic changes play a role in the pathogenesis of myeloid malignancies and hypomethylating agents have shown efficacy in these diseases. We studied the apoptotic effect, the genome-wide methylation and gene expression profiles in HL60 cells following decitabine treatment, using micro-array technologies. Decitabine treatment resulted in a decrease in global DNA methylation, corresponding to 4876 probeset IDs with significantly reduced methylation levels, while expression of 2583 IDs was induced. The integrated analysis identified 160 genes demethylated and upregulated by decitabine, mainly including development and differentiation pathways genes. Genes target of polycomb group protein regulation were overrepresented in this group. Apoptosis was induced by decitabine and apoptosis-specific PCR arrays more precisely indicated decitabine-induced upregulation of 13 apoptosis-related genes, in particular Dap-kinase 1 and Bcl2L10. Correspondingly, in primary patient samples, BCL2L10 was hypermethylated in 45% of AML, 43% of therapy-related myeloid neoplasms, 12% of MDS and in none of the controls.

2010-09-21 | GSE24224 | GEO

Homo sapiens

Project description:Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukaemia (AML)

| PRJNA88009 | ENA

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Project description:The FDA-approved DNA hypomethylating agents (DHAs) like 5-azacytidine (5AC) and decitabine (DAC) demonstrate efficacy in the treatment of hematologic malignancies. Despite previous reports that showed histone acetylation changes upon using these agents, the exact mechanism underpinning these changes is unknown. In this study, we investigated the relative potency of the nucleoside analogs and non-nucleoside analogs DHAs on DNA methylation reversal using DNA pyrosequencing. Additionally, we screened their effect on the enzymatic activity of the histone deacetylase sirtuin family (SIRT1, SIRT2, SIRT3, SIRT5 and SIRT6) using both recombinant enzymes and nuclear lysates from leukemia cells. The nucleoside analogs (DAC, 5AC and zebularine) were the most potent DHAs and increased the enzymatic activity of SIRT6 without showing any significant increase in other sirtuin isoforms. ChIP-Seq analysis of bone marrow cells derived from six acute myeloid leukemia (AML) patients and treated with the nucleoside analog DAC induced genome-wide acetylation changes in H3K9, the physiological substrate for SIRT6. Data pooling from the six patients showed significant acetylation changes in 187 gene loci at different chromosomal regions including promoters, coding exons, introns and distal intergenic regions. Signaling pathway analysis showed that H3K9 acetylation changes are linked to AML-relevant signaling pathways like EGF/EGFR and Wnt/Hedgehog/Notch. To our knowledge, this is the first report to identify the nucleoside analogs DHAs as activators of SIRT6. Our findings provide a rationale against the combination of the nucleoside analogs DHAs with SIRT6 inhibitors or chemotherapeutic agents in AML due to the role of SIRT6 in maintaining genome integrity and DNA repair.

2020-07-28 | GSE152804 | GEO

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